Apoptosis in Cancer

Cancer Letters xxx (2010) xxxxxx
Contents lists available at ScienceDirect
Cancer Letters
journal homepage: www.elsevier.com/locate/canlet
Targeting ER stress induced apoptosis and inammation in cancer

Tom Verfaillie, Abhishek D. Garg, Patrizia Agostinis *
Cell Death Research and Therapy Laboratory, Department of Molecular Cell Biology, Faculty of Medicine, Catholic University of Leuven, Belgium
a r t i c l e
i n f o
Article history:
Received 3 May 2010
Received in revised form 14 July 2010
Accepted 19 July 2010
Available online xxxx
Keywords:
ER stress
Unfolded protein response
Apoptosis
Cell death
Cancer
Anticancer therapy
Inammation
Antitumor immune response
a b s t r a c t
Disturbance in the folding capacity of the endoplasmic reticulum (ER), caused by a variety
of endogenous and exogenous insults, prompts a cellular stress condition known as ER
stress. ER stress is initially shaped to re-establish ER homeostasis through the activation
of an integrated intracellular signal transduction pathway termed as unfolded protein
response (UPR). However, when ER stress is too severe or prolonged, the pro-survival function of the UPR turns into a toxic signal, which is predominantly executed by mitochondrial
apoptosis. Moreover, accumulating evidence implicates ER stress pathways in the activation of various classical inammatory processes in and around the tumour microenvironment. In fact, ER stress pathways evoked by certain conventional or experimental
anticancer modalities have been found to promote anti-tumour immunity by enhancing
immunogenicity of dying cancer cells. Thus, the ER functions as an essential sensing organelle capable of coordinating stress pathways crucially involved in maintaining the crosstalk between the cancer cells intracellular and extracellular environment. In this review
we discuss the emerging link between ER stress, cell fate decisions and immunomodulation
and the potential therapeutic benet of targeting this multifaceted signaling pathway in
anticancer therapy.
2010 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
Abbreviations: AP1, activator protein 1; APR, acute-phase response;
ATF6, activating transcription factor 6; BFA, Brefeldin A; BiP, binding
immunoglobulin protein; CHOP, C/EBP homologous protein; COX, cyclooxygenase-2; CREBH, cyclic-AMP-responsive-element-binding protein H;
CRT, calreticulin; DAMP(s), Damage-associated Molecular Pattern(s); DC,
dendritic cells; eIF2a, eukaryotic initiation factor 2 Alpha; ER, endoplasmic reticulum; ERAD,
endoplasmic reticulum associated protein
degradation; GRP, glucose-regulated protein; HSP, heat shock protein;
IL, interleukin; IL-2R, interleukin 2 receptor; IRE1, inositol requiring
enzyme 1; JNK, c-jun N-terminal kinases; KEAP1, kelch-like Ech associated
protein 1; MAPK, mitogen-activated protein kinases; NF-jB, nuclear
factor kappa-light-chain-enhancer of activated B cells; Nrf2, nuclear
factor-E2-related factor 2; PDI, protein disulde isomerases; PDT, photodynamic therapy; PERK, pancreatic ER kinase (PKR)-like ER kinase; ROS,
reactive oxygen species; TLR(s), toll-like receptor(s); TNF, tumour
necrosis factor; TRAF2, tumour necrosis factor (TNF)-receptor associated
receptor 2; UPR, unfolded protein response; VEGF, vascular endothelial
growth factor; XBP1, X-box binding protein 1.
* Corresponding author. Address: Department of Molecular Cell Biology,
Faculty of Medicine, Catholic University of Leuven, Campus Gasthuisberg
ON1, Herestraat 49, B-3000 Leuven Belgium. Tel.: +32 16 345715.
E-mail address: patrizia.agostinis@med.kuleuven.be (P. Agostinis).
The endoplasmic reticulum (ER) is a central cellular

organelle that fulls crucial biosynthetic, sensing and
signaling functions in eukaryotic cells. Being responsible
for the synthesis, folding and posttranslational modications of proteins destined for the secretory pathway, the
ER has to maintain a tightly regulated oxidizing and Ca2+rich folding environment. Both protein folding as well as
Ca2+ buffering in the ER are assisted by various ER resident
chaperones like the glucose-regulated protein GRP78 (also
known as BiP), calreticulin, calnexin and protein disulde
isomerases (PDI). Various physiopathological conditions
like hypoxia, ER-Ca2+ depletion, oxidative injury, hypoglycemia and viral infections may affect ER homeostasis and
interfere with proper protein folding, ultimately causing
an imbalance between protein folding load and capacity.
This cellular condition is known as ER stress. The ER
responds to these perturbations by activating an integrated
0304-3835/$ - see front matter 2010 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.canlet.2010.07.016
Please cite this article in press as: T. Verfaillie et al., Targeting ER stress induced apoptosis and inammation in cancer, Cancer Lett. (2010),
doi:10.1016/j.canlet.2010.07.016
T. Verfaillie et al. / Cancer Letters xxx (2010) xxxxxx
signal transduction pathway, called the unfolded protein

response (UPR) [1]. The UPR (Fig. 1) is primarily tailored
to re-establish ER homeostasis by coordinating the temporal shut down in protein translation along with a complex
program of gene transcription that leads to the upregulation of components of the ER folding machinery and ER
quality control, like the ER-associated degradation (ERAD)
pathway. However, when ER stress is too severe or cannot
be solved, the UPR turns from a pro-survival to a pro-death
response, usually, but not uniquely, culminating in the
activation of intrinsic apoptosis [2]. In the next sections
we will briey discuss the dual role of the UPR in cellular
fates decision, since this subject has been exhaustively
discussed in recent reviews [3,4].
1.1. The UPR; a double faceted signal in cell death and survival
The UPR consists of a complex interplay between three
signaling arms, each of which emanates from a different
ER stress sensor; PERK (pancreatic ER kinase (PKR)-like

ER kinase), IRE1 (inositol requiring enzyme 1) and ATF6
(activating transcription factor 6). These are ER transmembrane proteins that are kept in an inactive state through
the direct association of their luminal domain with the
ER chaperone BiP/GRP78. Increasing levels of unfolded or
misfolded proteins in the ER lumen titrate BiP/GRP78 away
from these three sensors, allowing for the activation of
their signaling functions. PERK is a Ser/Thr kinase with
two known substrates thus far, eIF2a (eukaryotic initiation
factor 2) and the transcription factor Nrf2 (Nuclear factorE2-related factor 2) [5]. Under conditions of ER stress, the
PERK-mediated phosphorylation of eIF2a on Ser51 leads
to the inhibition of cap-dependent translation, thereby
reducing the protein load on the ER, while favouring
cap-independent translation. One UPR protein that is
selectively translated under these circumstances is the
transcription factor ATF4 [5]. The PERK-eIF2a-ATF4 axis
regulates the expression of several genes involved in ER
Fig. 1. UPR signaling pathways. ER stress is caused by an accumulation of unfolded proteins in the ER lumen. These unfolded proteins tether the ER
chaperone BiP/GRP78 away from its interaction with the three ER stress sensors PERK, IRE1 and ATF6 which become subsequently activated. Upon
activation, IRE1 mediates the unconventional splicing of XBP1 mRNA which encodes a transcription factor XBP1s, responsible for the upregulation of genes
involved in ERAD, ER quality control and redox homeostasis. Concomitantly, IRE1 can recruit TRAF2 and ASK1 to activate MAPK signaling pathways of p38
and JNK. PERK-mediated phosphorylation of the translation initiation factor eIF2a provides the cell with a temporary rest point by suppressing general
translation. Under these circumstances, ATF4 is selectively translated via cap-independent translation and upregulates proteins involved in ER homeostasis.
Upon BiP/GRP78 release, ATF6 is free to move to the Golgi where it is subsequently cleaved by local site1 and site2 proteases (S1P and S2P). The cleaved
fragment forms an active transcription factor that mainly mediates expression of several components for ERAD and ER homeostasis. Finally, persistent ER
stress can induce apoptosis. The pro-apoptotic transcription factor CHOP can be up-regulated by XBP1, ATF6 and PERK, and can mediate transcription of the
pro-apoptotic BH3-only protein Bim.
doi:10.1016/j.canlet.2010.07.016
homeostasis (e.g. BiP/GRP78 and GRP94), amino acid biosynthesis and transport functions, antioxidant stress responses as well as apoptosis. On the other hand, Nrf2
phosphorylation by PERK promotes the dissociation from
its cytosolic repressor KEAP1 (kelch-like Ech associated
protein 1), thereby freeing Nrf2 for nuclear translocation,
which ultimately results in the expression of a number of
genes implicated in the antioxidant stress response [6].
Thus the PERK branch of UPR bifurcates in two parallel
but integrated signaling pathways, PERK-eIF2a-ATF4 and
PERK-Nrf2, which favours the survival of ER stressed cells
by restoring ER quality control and increasing adaptation
to oxidative stress. Contrary to PERK, activated IRE1 displays both protein kinase (although there are no other direct substrates known besides IRE1 itself) as well as
endoribonuclease activity. IRE1 splices XBP1u mRNA (u
for unspliced) to form mature XBP1s mRNA (s for spliced)
which encodes a potent transcription factor XBP1s that
not only induces genes involved in ER quality control, ER/
Golgi biogenesis and certain ERAD components but also
genes involved in redox homeostasis and oxidative stress
response [7,8]. Finally, BiP/GRP78s release from ATF6 induces its translocation to the Golgi apparatus where it is
cleaved by specic Golgi resident proteases. Processing of
ATF6 produces an active transcription factor that apart
from targeting genes encoding ER chaperones and ERAD
components, also plays an important role in lipid biogenesis and ER expansion [9,10].
The basic mechanisms outlined thus far dene the initial pro-survival side of the UPR. When these early responses do not succeed in restoring ER homeostasis the
UPR tends to turn into a pro-death signal. Although the
molecular mechanisms underlying this switch remain
poorly understood, each apical UPR sensor holds a dualistic
role in propagating adaptive as well as toxic signals. A potential mechanism to explain this dichotomy may involve
the differential stability of pro-survival and pro-death
mRNAs/proteins under conditions of mild or severe ER
stress [11]. For instance, under mild ER stress, ATF4-dependent pro-survival gene expression is likely to be prevalent
since PERK is activated transiently and to a limited extent.
Here, because of the intrinsic instability of certain proapoptotic mRNAs and proteins, the apoptotic program
which is partially mediated by the ATF4 target CHOP (C/
EBP homologous protein, an important pro-apoptotic transcription factor, see further) would require a more sustained PERK activation associated with conditions of
more severe ER stress. This concept is supported by recent
studies showing that sustained PERK signaling is required
for the transition from protective to pro-apoptotic UPR
function [12]. As far as the IRE1 axis is concerned it is interesting to note that the general protective role for IRE1XBP1 signaling during mild ER stress is counterbalanced
by the scaffold signaling properties acquired by IRE1 independent of its XBP1 splicing activity. Here, under conditions of ER stress, IRE1 serves as a molecular platform for
the recruitment of the adaptor protein TNF-receptor associated factor 2 (TRAF2), an E3 ubiquitin ligase, that in turn
links IRE1 to the activation of the stress-activated ASK1JNK/p38 MAPK cascades, which have a dominant role in
cell fate decision as discussed below.
Irrespective of the exact mechanisms modulating the

functional activity of these apical UPR sensors, biochemical
and genetic evidence have assigned a crucial role to the
transcription factor CHOP in ER stress induced apoptosis
[13]. In fact, CHOP is a shared target gene of all three arms
of the UPR, as it can be induced by ATF4, cleaved ATF6 as
well as XBP1 (Fig. 1). CHOP mediates cell death through
the induction of various genes including GADD34 and
ERO1a, which may tip the balance towards apoptosis,
especially under conditions of unresolved ER stress.
GADD34, for example, is a regulatory subunit of protein
phosphatase 1 (PP1) that targets PP1 to dephoshorylate
eIF2a, thereby promoting resumption of protein synthesis.
However, if the protein folding capacity of the ER fails to be
re-established, a premature disinhibition of translation
will increase client protein load in the ER, thus amplifying
the damage [14]. Besides, induction of ERO1a can create a
hyperoxidizing ER environment, detrimental to protein
folding [15]. Thus the PERK-axis, which is involved in
maintaining the redox state during ER stress, as discussed
above, can turn into a pro-oxidant signal when the transcriptional program of CHOP is set in motion.
In addition, CHOP can also regulate the expression levels of some Bcl-2 protein family members [16,17], thereby
directly regulating the apoptotic machinery. Indeed, the
Bcl-2 family of proteins, known for their essential role in
the control of mitochondrial apoptosis, have been identied as vital regulators of ER homeostasis and participate
in UPR sensor mechanisms and cellular fate following ER
stress [18]. The pro-apoptotic multidomain proteins Bax
and Bak for example regulate ER Ca2+ levels, modulate
IRE1 activity through a direct and specic interaction with
this UPR sensor and are essential for the induction of mitochondrial apoptosis following ER stress [18]. While Bcl-2
proteins can alter IRE1 activity, activation of IRE1 leads
to the activation of MAPK/JNK which in turn can activate
certain BH3-only proteins like Bim or suppress the antiapoptotic activity of Bcl-2 [3]. In a similar way, CHOP can
promote the transcription of Bim [17] while suppressing
the induction of Bcl-2 [16]. In addition to Bim, other
BH3-only proteins, such as Noxa and Puma are transcriptionally activated, through p53-dependent [19] and independent mechanisms [20] depending on the type of ER
stressor. Interestingly, reconstitution of Bak expression at
the ER membranes in Bax/Bak decient MEFs could reestablish IRE1-TRAF2 activation and mitochondrial apoptosis mediated by reticular forms of the BH3-only proteins
Bim and Puma, thus bypassing the need to be localized to
the mitochondria [21]. This reticular form of Bak also engaged an atypical IRE1-TRAF2 activation pathway, wherein
the mobilization of Ca2+ promoted persistent JNK activation and mitochondrial apoptosis [21]. Furthermore, a recent report delineates JNK as a master regulator of both
apoptotic as well as autophagic pathways following ER
stress [22], thus providing further evidence of the complex
cross-talk between cell death and survival signals engaged
by the UPR.
In conclusion, the complex interplay between Bcl-2 proteins and UPR components seems to ne tune the UPR and
poises it as a central mediator of the decision between life
and death after ER stress.
doi:10.1016/j.canlet.2010.07.016
The execution of ER stressmediated cell death is crucially regulated by the cross-talk between pro-apoptotic
Bcl-2 family members residing both at the ER membrane
as well as the mitochondria and in most cases involves
the apoptosome-induced apoptosis, wherein caspase-9
functions as apical caspase in this cascade [18,23]. However, certain ER-associated caspases, which become processed and activated during ER stress, have been
implicated as well. For example, in rodents, activated
IRE1 provides a platform for the recruitment of caspase12 at the ER membrane and results in its proteolytic processing [24,25]. However, caspase-12 decient mouse
embryonic broblasts were found to display either no
resistance [25,26] or a partial protection specically
against ER stress inducing agents [27] an observation further extended to other cell lines exposed to different ER
stressors [28]. This suggests that although caspase-12 is
processed under conditions of ER stress, it may not be a
key mediator of ER stress induced apoptosis. Moreover,
the general relevance of this event is dubious, as functional
caspase-12 is only expressed in rodents, while in humans
mostly a truncated prodomain-only form or a full-length
caspase-12 get expressed but both are catalytically inactive [28] Moreover, caspase-12 belongs to inammatory
mediators so it is likely that it becomes processed as a result of apoptosis and may contribute to the regulation of
inammatory processes in cells undergoing ER stress. As
suggested by recent studies, caspase 4 might perform the
proposed functional role of caspase-12 in humans and contribute to the initiation of apoptosis following ER stress
[29,30]. Cleavage of BAP31, an ER transmembrane protein
involved in the transit of nascent membrane proteins between ER and cis-Golgi, by ER-associated caspase-8 results
in a p20 fragment that stimulates Ca2+ release from the ER
followed by uptake of Ca2+ into mitochondria, mitochondrial ssion and release of cytochrome c, precipitating
apoptosis [31]. This mechanism has been shown to contribute to apoptosis following ER stress caused by certain
anticancer agents, like the alkyl-lysophospholipid analogue edelfosine [32]. Interestingly, ER stress engaged by
anthracyclines results in the early cleavage of BAP31 by a
partially active form of caspase-8. This pre-apoptotic process is required for the mobilization of calreticulin from
the ER lumen to the plasma membrane (in case of selected
agents like anthracyclines), an event that has been shown
to confer a strong immunogenic character to the apoptotic
cell death process [33] (discussed further in Section 3.3.2).
1.2. UPR and autophagy: another way to survive?
Another important cellular mechanism that is activated
to cope with ER stress is macroautophagy (hereafter referred to as autophagy), a lysosomal pathway of protein
and organelle degradation in eukaryotic cells [34]. At its
basal rate, autophagy acts as a major housekeeping mechanism, crucially involved in the maintenance of normal
cellular homeostasis. When stimulated by cellular stress
conditions, autophagy can rapidly be up-regulated to cope
with an adverse environment. Characteristic for autophagy
is the appearance of the autophagosomes, double-membraned vesicles carrying cytoplasmic content that will
eventually be degraded after fusion with a lysosome.

Autophagy is a highly regulated process that is controlled
by a subset of evolutionarily conserved autophagy-related
genes (Atg). The molecular machinery of autophagy consists in its core of two kinase complexes, involving the
PI3K-Beclin 1 and ULK1/2-Atg13-mTOR systems, a shuttling protein and two ubiquitin-like conjugation systems
(reviewed in [34]).
The role of autophagy in ER stress is not completely
known and it is possible that when the proteasome-mediated degradation system is overloaded by the accumulation of unfolded proteins in the ER, autophagy would be
triggered to assist in removing them, thus serving as an
ER protein quality system (reviewed in [35]). Under these
conditions autophagy may have a cytoprotective role in
ER stress. In mammalian cells autophagy stimulation protects from ER stress induced by thapsigargin and tunicamycin. Likewise in yeasts, autophagy counterbalances ER
expansion, removes aggregated proteins from the ER and
improves overall survival [34,35]. Furthermore, autophagy
could prevent ER stress through the clearance of aggregated or toxic/diseased proteins accumulating in the cytosol, which cannot be removed by the proteasomal
degradation system. In agreement with this, autophagy
was found to be activated via a PERK-eIF2a mediated
mechanism involving the ATF4-mediated upregulation of
the autophagy gene Atg12, after ER stress induced by the
accumulation of polyglutamine (polyQ) proteins [36].
However, since in other systems PERK-independent eIF2a
phosphorylation induced by other eIF2a kinases like
PKR, HRI or GCN2, was also required to induce autophagy
[35], it is possible that the eIF2a-ATF4 axis rather than
PERK itself provides the molecular link between UPR and
autophagy.
Conversely, other studies implicated predominantly the
IRE1-branch of the UPR as mediator of autophagy after ER
stress [37,38]. One proposed mechanism relies on the activation of JNK subsequent to IRE1-TRAF2-ASK1 complex
formation. JNK has been shown to phosphorylate Bcl-2 at
the ER membrane, thereby disrupting its association with
the autophagy regulator Beclin 1 [39]. Moreover, JNK can
also directly regulate Beclin 1 expression [40]. Surprisingly,
XBP1 deciency caused a profound increase in autophagy
which enhanced the removal of superoxide dismutase 1
aggregates in an Amyotrophic lateral sclerosis model
[41]. This suggests that IRE1 RNase activity (XBP1 splicing)
and its scaffold function (activation of the TRAF2-JNK signaling) may play a differential role in the regulation of
autophagy.
ER stress is often accompanied by a release of Ca2+ into
the cytosol. Increased cytosolic Ca2+ levels may activate several Ca2+-regulated pathways leading to the activation of
various protein kinases, like AMPK, PKCh, and DAPK, which
have been shown to have a regulatory role in both apoptosis
and autophagy [4244]. In particular, DAPK has been shown
to phosphorylate Beclin 1 on the BH3-only domain, thus
preventing the interaction of this pro-autophagic protein
with Bcl-2 [45,46]. In this context it is interesting to note
that the scaffold properties of the inositol 1,4,5-trisphosphate receptor (IP3R), which can interact with both Bcl-2
and Beclin 1, rather than the Ca2+ mobilization function of
doi:10.1016/j.canlet.2010.07.016
this receptor, participate in the regulation of autophagy

[47]. Pharmacological inhibition or siRNA knockdown of
IP3Rs have been shown to stimulate autophagy thus suggesting that IP3R exerts a negative role in autophagy induction, probably by facilitating the inhibition of Beclin-1 by
Bcl-2. Consistent with this, NAF-1 (nutrient-deprivation
autophagy factor-1), a protein that binds Bcl-2 at the ER
and is required for Bcl-2 to functionally antagonize Beclin
1-mediated autophagy, has been identied as a component
of the IP3R receptor complex [48]. Although these molecular
interactions were not studied specically in the context of
ER stress, it seems that signaling pathways engaged by the
UPR converge in the regulation of a key node in the apoptosis-autophagy cross-talk the Bcl-2/Beclin 1 complex at the
ER membrane.
As mentioned above, the activation of autophagy by ER
stress has been functionally linked to increased adaptation
and survival [34,49]. However, just like in the case of the
UPR, stimulation of autophagy can also participate in the
mechanism of ER stress-induced cell death by either stimulating apoptosis or by inducing a form of non-apoptotic
cell death associated with lethal stimulation of autophagy
[49]. For example, in human glioma cells treated with the
D9-tetrahydrocannabinol (THC) the active component
of marihuana autophagy is activated via an ER stress
pathway involving eIF2a phosphorylation, and is required
to induce apoptotic cell death of the cancer cells [50]. On
the other hand, severe ER stress in cells with defects in
apoptosis signaling may lead to the aberrant stimulation
of self-digestion by autophagy, thereby committing the
cells to autophagic cell death [51]. Since apoptotic signaling in cancer cells is often affected, activation of non-apoptotic cell death pathways, like autophagic cell death,
represents an interesting alternative to kill tumour cells
with a promising therapeutic potential. The link between
ER stress and autophagy and how this knowledge can
add to cancer therapy has been extensively reviewed in
[49].
2. The UPR in cancer progression

An important hallmark of cancer is the uncontrolled
growth of the transformed cells [52]. As a result, solid tumours are continuously challenged by a restricted supply
of nutrients and oxygen due to insufcient vascularisation.
On the other hand, certain hematopoietic tumours often
display an increased production of certain secretory proteins, like is the case for multiple myeloma (MM) cells
which produce massive amounts of immunoglobulins
[53]. As discussed above, all these conditions impinge on
ER stress induction and subsequent activation of the UPR.
Indeed, increasing lines of evidence show that the UPR
plays an important role in tumour survival and tumour
progression under these circumstances.
The PERK-eIF2a-ATF4 axis for example, has proven to
be a critical factor in the adaptation of tumour cells to
hypoxic stress in vivo and in vitro (reviewed in [54]). Both
murine embryonic broblasts (MEFs) lacking PERK or
ATF4, as well as HT29 colorectal carcinoma cells expressing dominant negative PERK, display increased levels of
apoptosis under hypoxic conditions. Moreover, tumours

derived from transformed PERK-decient MEFs tend to
be much smaller due to a strongly reduced angiogenesis
[55]. Thus, the PERK-axis appears to drive carcinogenesis
by activating pro-survival mechanisms, which help cancer
cells to adapt to the hostile tumour microenvironment.
On the other hand, dormancy induced by the p38MAPK
in squamous cell carcinoma cells was associated with increased PERK activation, pointing to an additional role for
PERK in tumour growth suppression [56]. Indeed, translational arrest induced via eIF2a phosphorylation causes
down-regulation of several cell cycle regulators like cyclin
D1 resulting in subsequent cell cycle arrest [57]. In line
with this, a non-phosphorylable eIF2a-S51A mutant was
able to drive the malignant transformation of primary
human kidney cells and overexpression of GADD34 in
quiescent HEp3 cells restored tumour growth on the chorioallantoic membrane (CAM) of chicken embryos [56,58].
In conclusion, PERK activation seems to play an ambiguous role in tumour development and further research is
required to determine which PERK-mediated signaling
pathways affect crucial steps in tumour progression and
thus might be used to develop targeted therapies (as discussed further).
In addition to the PERK-eIF2a-ATF4 axis, increased
expression of the molecular chaperone BiP/GRP78 has been
implicated in carcinogenesis [59]. A causal correlation between BiP/GRP78 and carcinogenesis was supported by
earlier studies showing that BiP/GRP78- knockdown in
brosarcoma cells blocks their ability to form tumours
once xenografted in mice [60]. Further, BiP/GRP78 has
been found highly expressed in a variety of tumours
in vivo, likely as a result of the ER stress caused by the hypoxic and nutrient-deprived tumour microenvironment,
and its expression correlates with tumour growth, invasion
and metastatic potential [59].These observations suggest
that ER stress-mediated BiP/GRP78 expression in tumours
contributes to improved tolerance and cancer cells adaptation to tumour microenvironment. However, as in the case
of PERK, there are examples where increased BiP/GRP78
may rather play a tumour-suppressive role by inducing
dormancy [45] or senescence. For example, ER stress induced by the oncogene HRASG12V, one of the early oncogenic mutations found in certain melanocytic neoplasms
which are known not to progress to melanoma (the socalled Spitz naevi), drives premature senescence in primary human melanocytes through BiP/GRP78 and UPR
upregulation [61].This suggests that ER stress-mediated
BiP/GRP78 may be a molecular mechanism inhibiting
HRAS-driven transformation of normal human melanocytes [61]. Thus it is tempting to assume that increased
expression of BiP/GRP78 may have a differential role by
controlling local tumour growth in early tumour stages,
through stimulation of tumour suppressor mechanisms
like senescence or dormancy, while in more advanced
stages when tumours are exposed to severe chronic metabolic stress, would favour tumour progression through its
pro-survival and pro-metastatic functions.
Interestingly, preferential expression of BiP/GRP78 is
found both in the ER lumen as well as on the surface of tumour cells but not in normal organs, thus suggesting that
doi:10.1016/j.canlet.2010.07.016
surface BiP/GRP78 can have a role in signal transduction

mechanisms promoting cancer cell survival and growth.
In line with this, in prostate cancer cells, cell surface BiP/
GRP78 mediates the binding of the activated form of the
proteinase inhibitor a2-macroglobulin, leading to the
activation of the pro-survival and proliferative MAPK and
Akt-pathways [62]. On the other hand, in response to
TRAIL-mediated ER stress, a Par-4-BiP/GRP78 complex is
translocated to the cell surface. Par-4, a tumour suppressor
protein with a pro-apoptotic function, is spontaneously
secreted by cancer cells and through a positive feedback
loop able to bind to cell surface BiP/GRP78, resulting in
the activation of the extrinsic apoptotic pathway [63].
Furthermore, cell surface BiP/GRP78 may also serve as a
receptor for the angiogenesis inhibitor Kringle 5 (K5) of human plasminogen and high-afnity binding of K5 to BiP/
GRP78 is required for its antiangiogenic and pro-apoptotic
activity in stressed tumour cells and endothelial cells [64].
These observations suggest that besides its intracellular
cytoprotective function, BiP/GRP78 at the cell surface
may function as a high-afnity receptor for different
extracellular proteins modulating key signaling pathways
involved in survival and growth or apoptosis of the cancer
cells.
The importance of an intact UPR response for tumour
progression is also indicated by genetic studies showing
that, just like PERK, also IRE1 deciency results in similar
phenotypes under ischemic conditions. IRE1 decient
MEFs or tumour cells expressing a dominant negative
form of IRE1 are unable to induce vascular endothelial
growth factor A (VEGF-A) upregulation when deprived
of oxygen or glucose in vitro, causing reduced tumour
angiogenesis and growth in vivo [65]. This effect seems
to be predominantly mediated by XBP1 which is overexpressed in breast cancer, hepatocellular carcinoma, colorectal cancer as well as multiple myeloma. Moreover,
Carrasco et al. [66] showed that sustained overexpression
of XBP1 could drive plasma cells towards a premalignant
state in an El-xbp-1s transgenic mouse model. Interestingly, while loss of XBP1 was shown to inhibit tumour
growth as well as blood vessel formation, expression of
XBP1s restored angiogenesis in transgenic mice expressing a dominant negative IRE1 mutant. In addition, these
effects appeared to be independent from VEGF-A, indicating that XBP1 only partially regulates the pro-angiogenic
features of IRE1 [67,68]. Moreover, since VEGF-A secretion
under hypoxic conditions has been reported to be independent of PERK [69] a possible mediator of the IRE1
pro-angiogenic signal could be NF-jB, which is a key
transcription factor in the regulation of genes involved
in inammation (see further), cell death and survival,
but also angiogenesis [70]. Interestingly, NF-jB can be
activated through the recruitment and activation of IKK
by the IRE1-TRAF2 complex [71] (Fig. 2). In contrast, a recent study by Ghosh et al. [72] implicates all three arms
of the UPR and their effectors ATF4, cleaved ATF6 and
XBP1s, in the transcription of VEGF-A under ER stress
and hypoxia. Since this work was performed in cultured
cells studying mRNA levels, further studies will be required to explain the discrepancy with the results obtained for VEGF upregulation in vivo.
3. The UPR in cancer therapy

From a simplistic point-of-view one would like to promote severe ER stress in cancer cells by therapeutics that
either block the pro-survival pathways and/or promote
the pro-apoptotic signals emanating from the UPR. Unfortunately, molecular insights on life/death decisions during
ER stress are still too limited and the risk exists that the
anticancer drug in question might actually end up blocking
ER stress-mediated apoptosis, thereby promoting rather
than preventing tumour progression. This is a legitimate
concern if one considers the functional redundancy and
overlap between the three UPR pathways revealed so far
and the incomplete knowledge about the compensatory
mechanisms that may occur when one pathway is blocked
or down-regulated. Not surprisingly, there are conicting
data in the literature considering the impact of inhibiting
PERK or IRE1 in cancer therapy. In addition, present and future cancer therapies may have to take into account that
certain UPR-targeting modalities might end up hampering
the prospects of anti-tumour immunity (as discussed in
Section 3.2), thereby creating problems in integrating
anti-cancer immunotherapy within tumour-killing paradigms. Then again, certain modalities might actually have
the potential of augmenting anti-tumour immunity and
contribute to a more effective cancer treatment. A more
detailed discussion on this matter can be found in the later
sections.
3.1. Targeting the UPR in cancer therapy
Considering its important role in promoting tumour
growth and survival, PERK has been proposed as a valuable
therapeutic target in cancer therapy. However, as mentioned above, the role of PERK in tumour growth may not
be unambiguous and inhibition of certain UPR pathways
may result in altered signaling through the remaining
branches of the UPR. Indeed, HEK293 cells that overexpress
a kinase dead PERK mutant exhibit exuberant XBP1 splicing and robust cleavage activation of ATF6 in response to
ER stress, in an attempt to compensate for the lack of PERK
mediated pro-survival signaling [73]. Nevertheless, albeit
some delay these cells still induce CHOP to even supranormal levels, which partially accounts for their increased susceptibility to ER stress induced apoptosis [73]. On the other
hand, inducible and sustained activation of a Fv2E-PERK
fusion protein in HEK293 cells was shown to reduce cell
proliferation and stimulate apoptosis [12]. Similarly, activation of this Fv2E-PERK fusion protein in HEp3 and
SW620 colon carcinoma inhibited tumour growth in vivo
by inducing growth arrest [74]. Therefore, this growthinhibitory function of PERK has to be taken into account
when developing PERK targeted anticancer strategies,
since PERK inhibition might reinitiate proliferation of dormant tumours. Moreover, it was shown that the p38MAPK
can protect dormant tumours against drug-induced cytotoxicity via concomitant upregulation of BiP/GRP78 and
activation of PERK [56]. Interestingly, also ATF6 was shown
to be an important survival factor for dormant squamous
carcinoma cells. In these cells ATF6 transcriptionally
induces RHEB which then activates mTOR signaling
doi:10.1016/j.canlet.2010.07.016
Fig. 2. Schematic representation of main ER stress-/UPR- associated pathways leading to activation of pro-inammatory transcription program. ER stress
exerted by different agents/stressors leads to activation of the three UPR signaling arms; PERK, IRE1 and ATF6. Translational attenuation by the activated
PERK-eIF2a arm leads to an increase in the ratio of NF-jB to IjB, thereby freeing NF-jB to carry out its transcriptional role in the nucleus. On the other
hand, the IRE1-TRAF2 complex can recruit IjB kinase (IKK), which phosphorylates IjB, leading to its degradation and nuclear translocation of NF-jB, which
then regulates the expression of various pro-inammatory genes and immunomodulatory molecules/enzymes. Moreover, the IRE1-TRAF2 complex can
activate the JNK pathway leading to AP1-mediated transcriptional activation of different pro-inammatory genes. ER stress may cause CREBH (in case of
hepatocytes) and ATF6 to undergo the process of Regulated Intramembrane Proteolysis (RIP). Once cleaved, these activated fragments of CREBH/ATF6
form homodimers/heterodimers and transcribe genes coding for proteins that mediate acute-phase response.
independent from Akt, thereby rendering dormant cells

more resistant to chemotherapy [75]. Thus, under these
circumstances targeting ATF6 survival signaling likely represents a more valuable therapeutic approach.
In general, protein kinases like PERK, represent favourite targets for the development of small molecule inhibitors. IRE1, however, displays protein kinase as well as
endoribonuclease activity, thereby raising concerns about
the effects of inhibiting the kinase activity on splicing of
XBP1 and other downstream effectors. It has been established that the protein kinase activity of IRE1 is required
for TRAF2 recruitment during ER stress and therefore also
for JNK and NF-jB activation [71,76]. Moreover, IRE1s
RNase not only cleaves XBP1 mRNA but also regulates
the decay of many ER-localized mRNAs like those encoding
ER chaperones [77]. Interestingly, Han and co-workers
using different activation mutants of IRE1 showed that
ER stress, in combination with certain receptor protein
tyrosine kinase inhibitors like sunitinib and imatinib, can
activate IRE1 RNAse activity independent from its kinase

activity (i.e. autophosphorylation). This differentially active form of IRE1 can only cleave XBP1 while leaving other
ER-localized pro-survival mRNAs, like those encoding certain chaperones, intact. This results in their increased
translation and cytoprotective function, thereby counteracting apoptosis [78].
In conclusion, neither PERK nor IRE1, despite some
promising in vivo models, seem to be convenient targets
for cancer therapy. Moreover, some models discussed
thus far articially activate these sensors separately from
each other and outside an ER stress context, thereby raising doubts on their relevance in a true tumour microenvironment in which the UPR is often already activated. As
such, drugs that specically target the UPR response are
still in their infancy. However, in Section 4 we will describe some anticancer agents that in one way or the
other employ the UPR-targeting strategy in their mechanism of action.
doi:10.1016/j.canlet.2010.07.016
3.2. The UPR as a prognostic and diagnostic factor in cancer

Recent evidence indicates that molecular components
of the UPR could serve as prognostic and diagnostic
markers for cancer progression and response to chemotherapeutics.
BiP/GRP78 has been observed to be elevated in hepatocellular carcinoma, prostate, breast and gastric cancers
such that high BiP/GRP78 and XBP1 levels have been found
to correlate with higher pathological grade and aggressive
phenotype at least in case of breast cancer [79]. Additionally, autoantibodies against BiP/GRP78 have been observed
in sera of prostate cancer patients with aggressive disease
[80], suggesting that BiP/GRP78 might predict poor prognosis for the majority of solid tumours.
However, for lung cancer a positive expression of BiP/
GRP78 has been proposed to be indicative of favourable
prognosis [81]. Furthermore, positive BiP/GRP78 expression in neuroblastoma patients correlated with longer survival, an effect which may be related to the stimulation of
neuroblastoma differentiation by this glucose-regulated
protein [82]. Interestingly, a recent study analyzing the
association of BiP/GRP78 expression with tumour stage
and behaviour in esophageal adenocarcinomas found that
BiP/GRP78 was signicantly up-regulated in early cancers
and highly differentiated tumours as compared to more
advanced stages and normal tissue or less differentiated
tumours. Importantly, patients with higher BiP/GRP78
levels tended to show a survival benet [83]. Thus, as mentioned before, these studies point to a possible differential
role of UPR in tumour progression and advocate further
studies to clarify its prognostic and diagnostic value.
3.3. The role of anti-tumour immunity in UPR-targeted cancer
therapy
So far, the discussion on the role of UPR activation in
cancer progression and therapy has mainly focused on
intracellular events. However, over the past few years, substantial evidence has emerged that ER stress and UPR signaling might also be interconnected with inammatory
signaling pathways, thereby possibly affecting the outcome of various cancer treatments (see Fig. 2) [84]. For instance, XBP1 was recently proved to be an essential
component behind protecting C. elegans from the cellular
stress caused by instigating an immune response against
certain pathogens [85,86]. More specically, the UPR might
mediate certain classical inammatory processes like NFjB activation, acute-phase response (APR) and cytokine/
chemokine production as well as some emerging phenomena like anti-cancer vaccine effect. In the following sections we will briey discuss these new concepts on UPR
and inammation.
3.3.1. ER stress in cancer cells: activating the classical
inammatory signaling cascades
Several reports have linked UPR induction with production of various pro-inammatory molecules like IL-8, IL-6,
MCP-1 and TNF-a [87]. All three branches of the UPR have
been observed to mediate processes which lead to different
inammatory phenomena (see Fig. 2) which eventually,

may or may not prove to be anti-tumourigenic.
NF-jB is one of the central molecular mediators of
inammation. Recent studies have shown that all major
branches of the UPR may induce activation and nuclear
translocation of NF-jB (see Fig. 2) [84], which then induces
transcription of various genes coding for pro-inammatory
molecules [84,88] and enzymes, like cyclooxygenase-2
(COX-2) [89]. Moreover, oxidative stress as a result of ER
stress may also contribute to NF-jB activation. More specically, the PERK-eIF2a-mediated translational attenuation during ER stress can increase the ratio of NF-jB to
IjB, thereby freeing NF-jB to carry out its transcriptional
role in the nucleus (see Fig. 2) [90]. Simultaneously, ER
stress-induced IRE1a-TRAF2 complex can recruit IjB kinase (IKK), which phosphorylates IjB, leading to its degradation and nuclear translocation of NF-jB [71,76].
Moreover, the IRE1a-TRAF2-JNK cascade leads to the activation of the transcription factor activator protein 1 (AP1),
another known regulator of various pro-inammatory
genes [91]. Thus as apparent, there can be a signicant
amount of overlap between these different UPR branches
in terms of NF-jB activation.
The acute-phase response (APR) on the other hand, is
essentially an intricate and broad immunological process
involving all four classical signs of inammation swelling, redness, heat and pain compounded by signs of sickness behaviour (i.e. systemic psychological effects of
local inammation) [92,93]. APR is associated with various
distinct markers/manifestations like neutrophilia, pituitary-adrenal hormonal axis activation and production of
cytokines like IL-1b, IL-6, and IL-2R [93,94]. The link
between APR and ER stress is mainly mediated by two molecules i.e. ATF6 and cyclic-AMP-responsive-element-binding protein H or CREBH (where, CREBH is mainly expressed
in hepatocytes) [84]. Upon ER stress, ATF6 and CREBH trafc from the ER to the Golgi complex, where they are
cleaved (mainly by enzymes like S1P and S2P) to release
their respective functional isoforms, through a process
known as Regulated Intramembrane Proteolysis (RIP)
[84,95]. Once these activated fragments of CREBH and
ATF6 are formed (Fig. 2), they translocate into the nucleus
and induce transcription of APR genes, like those encoding
for C-reactive protein and serum amyloid P (SAP) component [84,96]. It should be noted that, CREBH-mediated
APR mainly exists in the liver [84]. Also it is worth mentioning here that, photodynamic therapy (PDT), which induces UPR pathway(s) in cancer cells [97], has been
shown to induce APR as well as neutrophilia during cancer
treatment, in vivo [94] (reviewed in [98,93]). APR-associated neutrophilia could be vital for overall anti-tumour
immunity, since active neutrophils have the ability to
inuence DC maturation, present antigens derived from
tumour cells to CD4+ T cells as well as secrete alarmins,
cytokines and chemokines [93,99]. However, further
research is required to ascertain as to how this ER stressAPR link might be exploited for therapeutic purpose.
It is also very important to consider that there are no
certainties that ER stress/UPR driven induction of various
pro-inammatory pathways (discussed above) would
actually stimulate potent anti-tumour immunity. As a
doi:10.1016/j.canlet.2010.07.016
matter of fact, since it is now generally accepted that

strong inammation could actually be pro-tumourigenic
in most situations (except in certain cases like, bladder carcinoma) the maintenance of inammatory microenvironment could be considered to be an essential component
of all tumours [100]. This notion receives some substantiation from the fact that, NF-jB and AP1 whose activations
are mediated by ER stress/UPR branches (as discussed
above), have been found to play a major role in inammation-driven tumour-promotion due to their ability to induce expression of tumour-promoting cytokines [100].
In fact, several studies have shown that NF-jB inhibition
in metastatic cancer cells can convert inammation-promoted tumour growth into inammation-induced tumour
regression (IFN-induced and TRAIL dependent) [101]. Thus,
it might be interesting to see, if in the future we could exploit our knowledge of UPR pathways leading to NF-jB
activation to ultimately target NF-jB-mediated signal in
the tumour microenvironment.
Even though the above observations hold true in many
situations, yet the net outcome of anti-tumour therapy-induced inammation is still considered to be controversial,
since on one hand it can be tumour-promoting yet on another it can be anti-tumourigenic [100]. Best example that
could represent this conundrum emerged recently. Development of colon cancer driven by ulcerative colitis (UC)
is considered to be the best clinically characterized example of inammation-driven tumourigenesis [102]. However, recently it was shown that PYCARD, caspase-1 and
NLRP3, the three important components of NLR inammasomes (a protein complex within immune cells that instigates various pro-inammatory pathways) actually help
in resisting the development of colon cancer [102]. Based
on this complexity, one can safely assume that anti-tumour immunity and tumour-promoting inammation
coexist at different times during tumours progression/
development [100].
3.3.2. ER stress in cancer cells: from cell death to
augmentation of cell deaths immunogenicity
In recent years, it has been shown that certain chemotherapeutic agents could not only kill the cancer cells (in
predominantly apoptotic manner) but could also increase
the overall immunogenicity of their cell death, thereby
offering the possibility of reducing the immunosuppression in and around the tumour microenvironment [103].
Such a cell death is usually termed as immunogenic cell
death of which necrosis is the best characterized type
and another type that has recently emerged is immunogenic apoptosis [103]. Usually, the immunogenicity of dying cells is dened by various molecules categorized under
the umbrella term Damage-associated Molecular Patterns (DAMPs) [103,104]. DAMPs are mostly dened as
intracellular molecules which are retained within the cells
under normal conditions but tend to acquire immunostimulatory/pro-inammatory activity, once secreted or exposed outside by the damaged/dying cells [103,104].
Immunogenic apoptosis is a newly described cell death
process induced by certain selected agents (like anthracyclines, oxaliplatin, UVC irradiation, ionizing irradiation
and Bortezomib), which unlike the classical apoptosis,
tends to have pro-inammatory/pro-immunological properties and the capability of inducing DC-based anti-cancer
vaccine effect [103]. This capability of being able to combine the physiological cell death mechanism with potent
revival of anti-tumour immunity makes the concept of
immunogenic apoptosis attractive. Needless to say, this
also makes the signaling pathways and molecules associated with immunogenic apoptosis vital.
Recent studies showed that two DAMPs-based processes were critical for induction of immunogenic apoptosis i.e. increased surface exposure of calreticulin or
ecto-CRT (in case of anthracyclins, oxaliplatin, UVC irradiation, ionizing irradiation) and surface exposure of heat
shock protein 90 or ecto-HSP90 (in case of Bortezomib)
such that the absence of ecto-CRT or ecto-HSP90 abrogated
the anti-cancer vaccine effect and anti-tumour immunity
respectively [105107]. Interestingly, it has been shown
that in case of ecto-CRT exposure, ER stress was vital for
its surface translocation [33,103]; such that the considerably complex pathway mediating ecto-CRT/ERp57 exposure on dying cells circled around the ER [33,106]. This
pathway consisted of ER Ca2+-leakage, PERK-mediated
eIF2a phosphorylation (on serine 51), followed by a preapoptotic and partial activation of caspase-8. Later, the
cleavage of the caspase-8 substrate BAP31, an ER-sessile
protein, along with conformational activation of Bax and
Bak, was required and accompanied by movement of
CRT/ERp57 through Golgi bodies and SNARE-dependent
exocytosis, towards the surface [33]. Hence, in light of
the currently available data about the mechanisms of surface translocation of DAMPs, an attractive possibility
would be to consider ER stress inducing agents as the initial stepping stones towards creating a library of compounds capable of inducing immunogenic cell death [103].
4. Cancer drugs affecting ER stress pathways
Emerging evidence suggests that agents affecting the
UPR could be exploited as promising anticancer drug candidates. Because of the dualistic role of the UPR in cell survival and death, and depending on the type of tumour,
compounds that either induce severe ER stress and cell
death, or agents blocking the cytoprotective function of
the altered UPR of cancer cells, could be used either alone
or in combination with conventional anticancer treatments. Along with a growing interest in the UPR as therapeutic target, in the last few years major effort has been
directed to drug discovery and development of strategies
to identify and characterize new compounds with the ability to induce cancer cell death by targeting the UPR [108].
Here below we discuss some interesting UPR-suppressing
and UPR-inducing agents that have been recently added
to the list of promising anticancer agents/strategies.
4.1. Proteasome inhibitors
To survive ER stress, cells rely on the ERAD pathway, by
which terminally misfolded proteins are retrotranslocated
to the cytosol and targeted for degradation by the 26S proteasome. This multicatalytic protease regulates expression
doi:10.1016/j.canlet.2010.07.016
10
levels of most intracellular proteins including those regulating cell proliferation and apoptosis. Blocking this proteasome will increase the protein burden on the already
challenged ER often encountered by tumour cells as described above and this could possibly tilt the balance towards apoptosis, a notion that has proven to be a
valuable therapeutic approach for cancerous malignancies
[109].
Thus far, Bortezomib or Velcade represents the best
characterized proteasome inhibitor that has reached successful clinical trials. By itself, Bortezomib seems to be
most effective against various types of hematopoietic tumours like multiple myeloma as well as cancer types derived from cells with a specialized secretory function like
pancreatic tumours, which already rely on an augmented
UPR for their survival [110]. For large solid tumours however, a combinatorial approach seems more appropriate.
Since hypoxic tumour cells are particularly sensitive to
proteasome inhibition, this paradigm could be combined
with anticancer therapies targeting the normoxic fraction
of human tumours [111]. Indeed, the combination of cisplatin (shown to induce ER stress) and Bortezomib (shown
to induce ER stress while simultaneously inhibiting the
UPR) caused a severe sensitization of pancreatic cancer
cells to ER stress induced apoptosis [112]. Some cancer cell
lines however succeed at adapting to Bortezomib treatment, in part through an increase in the activity/expression
of different proteasome subunits [113]. Also in this case,
combinatorial treatment seems capable of overcoming
these restrictions since Bortezomib has been successfully
used in combination with the HIV protease inhibitor Ritonavir in Bortezomib-resistant Sarcoma cells [114]. In general, one could postulate that Bortezomib could be used
in combination with any sort of therapy that induces ER
stress, pushing misfolded proteins over the threshold
levels a cell cannot cope with. For example, PDT with the
photosensitizer Photofrin induces ER stress and in combination with Bortezomib causes a strong sensitization of tumour cells to cell death both in vitro and in vivo [97].
Finally the successful implementation of Bortezomib in
various anticancer routines has lead to the development
of several new second generation proteasome inhibitors
like the Bortezomib analogues MLN9708 and CEP18770
[115].
4.2. Brefeldin A
From the promising results obtained with proteasome
inhibitors, it can be postulated that provoking an ER overload represents an interesting therapeutic strategy. This
idea led to the design of therapeutic paradigms targeting
the secretory pathway. One such drug is Brefeldin A
(BFA), which prevents coatamer assembly onto Golgi
membranes, thereby blocking retrograde transport, which
causes an accumulation of trapped secretory proteins in
the ER and subsequent activation of the UPR. However,
although some promising work has been done in vitro, data
on successful application of BFA in vivo are still very scarce.
One possible culprit is the limited solubility/stability of
BFA that prevents its direct administration in a clinically
acceptable formulation. Therefore, a water soluble and
more stable prodrug called Breate was developed that

showed promising results against several human melanoma xenografts in nude mice [116].
BFA induces apoptosis in several human cancer cell
lines like Leukemia (HL60 and K562) and colon carcinoma
(HT-29) [117], prostatic adenocarcinoma [118], Jurkat T
cells [119] and neuroendocrine tumour cells [120] and
shows antitumor activity in human melanoma xenografs
in athymic mice [121]. Similar to the proteasome inhibitors, cells that rely on a more extensive ER network for
their survival, like chronic lymphocyte leukemia (CLL)
and multiple myeloma cells are particularly more sensitive
to BFA induced apoptosis than non-transformed B cells
[122]. However, when considering BFA for combinatorial
therapy, an important consideration must be made. Various drugs/treatments commonly used in cancer therapies,
like TRAIL, doxorobucin, vincristine and irradiation, have
recently been shown to depend on Par-4 to induce apoptosis in cancer cells [63,123]. As mentioned before, Par-4,
which is secreted by cancer cells via a BFA-sensitive pathway, can induce extrinsic apoptosis by binding to BiP/
GRP78 expressed at the surface of cancer cells [63]. Thus,
blocking this cell death pathway by BFA co-administration
may reduce rather than increase the therapeutic benet of
a combinatorial therapy.
4.3. Hsp90 inhibitors

Hsp90 is an important molecular chaperone that stabilizes various proteins like BCR-ABL, cRAF, BRAF, Akt and
VEGFR that are known to play an important role in oncogenesis. Thus, Hsp90 represents an interesting therapeutic
target since blocking its function may cause a simultaneous inhibition of several important signal transduction
pathways. Indeed, several rst-generation inhibitors, like
the geldanamycin analogues 17-AAG (tanespimycin) and
its derivative 17-DMAG (alvespimycin), have reached
phase I and II clinical trials and a second generation of
inhibitors is being developed [124]. Interestingly, Hsp90
was also shown to interact with the cytosolic domains of
PERK and IRE1 and its inhibition caused the proteasomal
degradation of both existing and newly synthesized pools
of these proteins [125]. Treatment of myeloma cells with
two different Hsp90 inhibitors, 17-AAG and radicicol, induced ER stress and subsequent activation of the three
arms of the UPR which, at least partially, contributed to cell
death of the treated cells [126]. However, induction of
apoptosis in myeloma cells by another Hsp90 inhibitor
IPI-504 appeared to be mediated by a partial inhibition of
the UPR, rather than activation, again accounting for the
fact that blocking the UPR in secretory cells severely hampers their survival [127]. The contradictory results reported using various Hsp90 inhibitors likely reects the
broad specicity of these inhibitors towards other Hsp90
related chaperones. Indeed, Marcu and co-workers could
already show that the induction of BiP/GRP78 after treatment with geldanamycin was caused by inhibition of
GRP94, an ER localized member of the Hsp90 chaperone
family, while treatment with the Hsp90 specic inhibitor
514 failed to induce BiP/GRP78 [125].
doi:10.1016/j.canlet.2010.07.016
4.4. Targeting BiP/GRP78 in cancer therapy

Accumulating evidence indicates that, ER stress mediated induction of BiP/GRP78 preferentially in cancer cells
can confer protection against anticancer drugs, through
different mechanisms including direct interference with
the apoptotic machinery [59]. Based on this premise, it is
conceivable that compounds that either suppress stress
induction of BiP/GRP78 or its catalytic function may sensitize cancer cells to a variety of therapeutic agents. In line
with this, knockdown of BiP/GRP78 has been shown to sensitize malignant glioma cells to the therapeutic temozomolide [128], etoposide- and cisplatin treatment [129].
Likewise, the macrocyclic compound versipelostatin
(VST), which inhibits BiP/GRP78 transcriptional activation
by glucose-deprivation [130], inhibits tumour growth of
stomach cancer xenograft when combined with cisplatin
[131].
In the highly chemoresistant metastatic melanoma,
down-regulation of BiP/GRP78 by siRNA or treatment
with the BiP/GRP78-specic subtilase toxin enhances
apoptosis following the ER stress inducing agents fenretinide or bortezomib [132]. Furthermore, BiP/GRP78 has
been shown to serve as the intracellular target for melanoma differentiation-associated gene-7/interleukin-24
(mda-7/IL-24), an IL-10 family cytokine localizing in the
ER and able to induce cancer-selective growth suppression and apoptosis in a wide spectrum of human cancers
and animal models [133]. Moreover, in addition to proliferating tumour cells, up-regulation BiP/GRP78 has been
shown to confer drug resistance selectively to dormant
tumour cells, by interfering with Bax-mediated activation
of apoptosis [56]. All together these studies suggest that
strategies to down-regulate/inhibit BiP/GRP78 may represent promising therapeutic approaches for enhancing
chemosensitivity in several cancers.
In addition to this, the restricted expression of BiP/
GRP78 at the plasma membrane of the cancer cells makes
it an attractive target for the development of new therapeutic tactics, such as mAb-based immunotherapies, targeting cancer cells to self destruction, while sparing
healthy tissues. One of such strategies consists in the systemic administration of synthetic chimeric peptides with
BiP/GRP78 binding motifs fused to a pro-apoptotic sequence or cytotoxic drug, as a delivery vehicles targeting
human cancer cells in a strictly BIP/GRP78-dependent
manner [134]. This mechanism has been shown to suppress tumour growth in xenograft models of breast and
prostate cancer [135]. Secondly, tactics aimed at reducing/suppressing the binding of cell surface BiP/GRP78 to
extracellular molecules involved in cancer cell proliferation and metastasis (e.g. activated a2-macroglobulin) or,
on the other hand, at favouring the binding of BiP/GRP78
to antiangiogenic or pro-apoptotic molecules (e.g. K5 or
Par-4) are being considered (reviewed in [59]).
4.5. Anti-tumour immunity and drugs affecting ER stress
pathways: Time to come of age?
Several drugs which target one or more branches of the
UPR pathway are currently under-development and it is
11
expected that they would rapidly mature from bench-side

to bed-side in the coming years [49,84,136]. However, consideration on the effects of these agents on ER stress-associated inammatory/immunostimulatory pathways has
been seldom paid during their development. This is not
surprising in the light of the fact that the capabilities of
ER stress in augmenting anti-tumour immunity have only
recently received sizeable attention and this link is also
considerably unexplored (mainly due to its complexity).
In our opinion, considering the recent strong evidence as
to how ER stress-mediated surface translocation of DAMPs
can mediate various anti-tumourigenic immunological
processes (discussed above), it might be crucial to select
those UPR-targeting modalities which either encourage
anti-tumour immunity or at least dont inhibit or suppress
it.
In a holistic sense, while some of these agents might
actually be good in terms of increasing the immunogenicity of the cancer cell death pathway and/or anti-tumourigenic inammation (e.g. Bortezomib, curcumin, celecoxib,
PDT) yet certain other agents might in reality decrease
them (e.g. BFA, Hsp90 inhibitors). An overview of pros
and cons of certain UPR-targeting/inducing agents or
therapies capable of affecting the immune system has
been discussed in Table 1. It is important to note here
that apart from immunomodulatory effects on the cancer
cells induced by these therapeutic agents, effects on tumourassociated/-inltrating immune cells, also tend to
matter (in fact could be more crucial). For example, B
cells require UPR components for differentiating into antibody-secreting cells and also they tend to have a signicant protein load in the ER [86], thus, any therapeutic
agent that inhibits/suppresses UPR branches in the tumour microenvironment (and around), might affect antibody-mediated immunity [84,136]. Moreover, UPR
components might also play an important role in signaling pathways associated with Toll-like receptors (TLRs),
the major foreign/pathogen/non-self pattern sensing
receptors of the innate immune system [86]. It was recently shown that, stimulation of TLR1-TLR2 or TLR4
receptors on mouse macrophages results in IRE1 activation and XBP1 splicing [86,137], resulting in a XBP1-mediated induction of various pro-inammatory cytokines
[86,137]. Furthermore, prolonged ER stress may also affect immunoglobulin-associated immunity by causing
mislocalization of Ig immunoglobulin proteins into the
cytoplasm [138]. Similarly, agents like BFA (see Table 1)
could affect the overall spectra of cytokines and chemokines [139] within the tumour microenvironment thereby
creating possible problems. Here, as evident from Table 1,
out of the different ER stress-/UPR- targeting modalities
that have been found to be promising, PDT based on an
ER localizing photosensitizer (like hypericin) stands out
in terms of combining effective tumour cell death
(induced via ER stress/UPR) with potential revival of
anti-tumour immunity [49,93,103]. However, further
investigations are required to ascertain whether such a
PDT paradigm could induce anti-cancer vaccine effect
backed up by immunogenic cancer cell death involving
surface translocation/extracellular secretion of various
DAMPs.
doi:10.1016/j.canlet.2010.07.016
12
Table 1
ER stress-/UPR- targeted therapeutic modalities and their pros and cons in terms of anti-tumour immunity and immunogenic cancer cell death.
Therapeutic agent/
modality
Therapeutic effect related to ER stress/UPR
Pros and/or Cons
References
Bortezomib
A proteasome inhibitor, which creates ER stress by

overwhelming the ER-associated degradation
(ERAD) pathway with misfolded proteins
[103,107,136]
Brefeldin A (BFA)
BFA is an ER-to-Golgi transport inhibitor which can

induce UPR by overwhelming ER with proteins that
would be normally trafcked to Golgi complex
Curcumin
Curcumin is a natural compound with the ability to

induce cell cycle arrest and apoptosis. It has been
found to be capable of inducing apoptosis via ER
stress pathway
Celecoxib
Celecoxib is an inhibitor of cyclooxygenase-2 (COX2) enzyme that can induce ER stress pathways as
well as tumour cell death
Ritonavir
It is a HIV protease inhibitor, which can interfere

with the ERAD machinery and activate certain UPR
components
HSP90 inhibitors
HSP90 inhibitors can activate all three UPR

branches and ER stress as well as cancer cell death
BiP/GRP78
inhibitors/
de-activators
Versipelostatin and Subtilase are two modalities

which have been recently proposed to inhibit or
cleave BiP/GRP78 respectively, thereby
inactivating it
Photodynamic
therapy (PDT)
PDT is an established anticancer modality utilizing

the destructive power of reactive oxygen species
generated via visible light irradiation of a
photosensitive dye accumulated in the cancerous
tissue/cells, to bring about their obliteration. PDT
has been found to be a major inducer of cell death
via ER stress and UPR signaling
Bortezomib can help in surface translocation of

HSP90, a potential DAMP, which was further found
to enhance dendritic cell (DC)-based anti-tumour
immunity
BFA could prove to be a major suppressor of both
immunogenicity of cancer cell death pathway(s)
and tumour-associated inammation. BFA can
inhibit/down-regulate anti-cancer vaccine effect as
well as surface exposure of CRT. BFA can also inhibit
any kind of cytokine/chemokine secretion from the
treated cancer cells or immune cells
Curcumin has potent immunomodulatory
properties such that it can modulate the activation
of various immune cell like macrophages,
neutrophils, natural killer cells, DCs, B cells and T
cells. It can also enhance antibody responses at
lower doses
COX-2 plays a vital role in prostaglandin E2 (PGE2)
biosynthesis which is a potent immunosuppressive
molecule that assists in tumour angiogenesis,
metastasis and tumour-induced immune
dysfunction. A drug like celecoxib that inhibits
COX-2 and induces tumour cell death at the same
time could be vital
Ritonavir has been found both to improve antibody
response and to inhibit CD8+ T cell activity. The net
effects of this drug on tumour microenvironment
have not been investigated fully, yet
Surface exposure of HSP90 on dying cancer cells has
been implicated in augmenting the immunogenicity
of these dying cells thereby making HSP90 a
critical DAMP. Geldanamycin (an HSP90 inhibitor)
can abrogate this immunogenicity thereby raising
doubts on this modality. Besides, there is some
speculation that HSP90 inhibitors might indeed
prove to be immunosuppressive in long run
Although not much is known about the
immunological effects of Versipelostatin-based BiP
inhibition, researchers have shown that Subtilasebased cleavage of BiP/GRP78 can block antibody
secretion in B cells, since BiP/GRP78 is vital for
antibody secretion machinery. Thus, further
analysis is needed to ascertain the immunological
consequences of BiP/GRP78 inhibitors systemically
or in tumour microenvironment
PDT mediates various immunological processes in
and around the treated site like neutrophilia,
acute-phase response as well as activation of
various immune cells, complement cascade and
production of cytokines/chemokines. PDT causes
also surface exposure/extracellular release of
DAMPs like HSP70, and is capable of activating
anti-tumour adaptive immunity in both preclinical as well as clinical settings
5. Concluding remarks
As outlined above, the ER is a central organelle in the
maintenance of cellular homeostasis. Not surprisingly, a
disturbed or malfunctioning ER, a condition associated
with ER stress- is linked to different diseased conditions
such as cancer and underlies the pro-apoptotic mechanism
of certain anticancer modalities. However, the molecular
mechanisms activated by ER stress are not straightforward
and involve signaling pathways with dualistic function in
[33,103,139]
[136,140]
[93,136]
[136,141]
[103,107,136,142]
[130,143]
[49,93]
cell survival and death. Thus, decoding how ER stress pathways signal to cell death or prevent it constitutes a major
challenge for future investigations and will be required,
to dene a rationale for drug design and applications. In
this perspective, small molecules inhibitor of the kinasecomponents of the UPR, like PERK and IRE1, are promising
druggable candidates. The challenge for cancer treatment
will consist in the development of drugs targeting the cytoprotective function of the UPR, while leaving intact or
potentiating its pro-apoptotic function. Moreover, in the
doi:10.1016/j.canlet.2010.07.016
last few years several studies have evidenced that ER stress

is closely related to and/or inuences inammatory and
immunological responses and can have a major impact
on the immunogenicity of the cell death process elicited
by certain anticancer therapeutics or modalities. Thus, in
the future it seems very important to integrate the proimmunological potential of ER stress/UPR pathways with
the current therapeutic (cell killing) paradigms which are
trying to target it or at the very least, care ought to be taken that the selected agents do not suppress potent antitumour immunity.
[15]
[16]
[17]
[18]
6. Conict of interest statement

The authors have no conict of interest to declare.
Acknowledgements
This work was supported by Grants to P.A. from the K.U.
Leuven (OT49/06) F.W.O Vlaanderen (G.0661.09) and
Interuniversity Attraction Pole (IAP) 6/18 initiated by the
Belgian State, Science Policy Ofce. Lastly, all gures were
produced using Servier Medical Art (www.servier.com) for
which the authors would like to acknowledge Servier.
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Apoptosis in Cancer

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Cancer Letters xxx (2010) xxxxxx

Contents lists available at ScienceDirect

Targeting ER stress induced apoptosis and inammation in cancer

The endoplasmic reticulum (ER) is a central cellular

T. Verfaillie et al. / Cancer Letters xxx (2010) xxxxxx

signal transduction pathway, called the unfolded protein

ER stress sensor; PERK (pancreatic ER kinase (PKR)-like

T. Verfaillie et al. / Cancer Letters xxx (2010) xxxxxx

Irrespective of the exact mechanisms modulating the

T. Verfaillie et al. / Cancer Letters xxx (2010) xxxxxx

eventually be degraded after fusion with a lysosome.

T. Verfaillie et al. / Cancer Letters xxx (2010) xxxxxx

this receptor, participate in the regulation of autophagy

2. The UPR in cancer progression

apoptosis under hypoxic conditions. Moreover, tumours

T. Verfaillie et al. / Cancer Letters xxx (2010) xxxxxx

surface BiP/GRP78 can have a role in signal transduction

3. The UPR in cancer therapy

T. Verfaillie et al. / Cancer Letters xxx (2010) xxxxxx

independent from Akt, thereby rendering dormant cells

activate IRE1 RNAse activity independent from its kinase

T. Verfaillie et al. / Cancer Letters xxx (2010) xxxxxx

3.2. The UPR as a prognostic and diagnostic factor in cancer

inammatory phenomena (see Fig. 2) which eventually,

T. Verfaillie et al. / Cancer Letters xxx (2010) xxxxxx

matter of fact, since it is now generally accepted that

T. Verfaillie et al. / Cancer Letters xxx (2010) xxxxxx

more stable prodrug called Breate was developed that

4.3. Hsp90 inhibitors

T. Verfaillie et al. / Cancer Letters xxx (2010) xxxxxx

4.4. Targeting BiP/GRP78 in cancer therapy

expected that they would rapidly mature from bench-side

T. Verfaillie et al. / Cancer Letters xxx (2010) xxxxxx

Therapeutic effect related to ER stress/UPR

Pros and/or Cons

A proteasome inhibitor, which creates ER stress by

BFA is an ER-to-Golgi transport inhibitor which can

Curcumin is a natural compound with the ability to

It is a HIV protease inhibitor, which can interfere

HSP90 inhibitors can activate all three UPR

Versipelostatin and Subtilase are two modalities

PDT is an established anticancer modality utilizing

Bortezomib can help in surface translocation of

T. Verfaillie et al. / Cancer Letters xxx (2010) xxxxxx

last few years several studies have evidenced that ER stress

6. Conict of interest statement

ation of the alpha subunit of eukaryotic translation initiation factor

T. Verfaillie et al. / Cancer Letters xxx (2010) xxxxxx

[35] M. Hoyer-Hansen, M. Jaattela, Connecting endoplasmic reticulum

[54] D.R. Fels, C. Koumenis, The PERK/eIF2alpha/ATF4 module of the UPR

T. Verfaillie et al. / Cancer Letters xxx (2010) xxxxxx

survival of cells compensating for deciency in the ER stress

of CREBH to induce a systemic inammatory response, Cell 124

T. Verfaillie et al. / Cancer Letters xxx (2010) xxxxxx

[117] R.G. Shao, T. Shimizu, Y. Pommier, Brefeldin A is a potent inducer of

response via aberrant activation of 4E-binding protein 1 by

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