Seminars in Cancer Biology 33 (2015) 5766

Contents lists available at ScienceDirect

Seminars in Cancer Biology

journal homepage: www.elsevier.com/locate/semcancer

Review

Controlling the unfolded protein response-mediated life and death

decisions in cancer
Marion Maurel a,c , Eoghan P. McGrath a , Katarzyna Mnich a , Sandra Healy a , Eric Chevet b,c ,
Afshin Samali a,
a

Apoptosis Research Centre, National University of Ireland, Galway, Ireland

Inserm U1052, F-33000, University of Bordeaux, Bordeaux, France
c
Centre de Lutte Contre le Cancer Eugne Marquis, 35000 Rennes, France
b

a r t i c l e

i n f o

Keywords:
Apoptosis
Cancer
Cell death
ER stress
UPR

a b s t r a c t
Cancer cells are exposed to intrinsic (oncogene) or extrinsic (microenvironmental) challenges, leading
to activation of stress response pathways. The unfolded protein response (UPR) is the cellular response
to endoplasmic reticulum (ER) stress and plays a pivotal role in tumor development. Depending on ER
stress intensity and duration, the UPR is either pro-survival to preserve ER homeostasis or pro-death if the
stress cannot be resolved. On one hand, the adaptive arm of the UPR is essential for cancer cells to survive
the harsh conditions they are facing, and on the other hand, cancer cells have evolved mechanisms to
bypass ER stress-induced cell death, thereby conferring them with a selective advantage for malignant
transformation. Therefore, the mechanisms involved in the balance between survival and death outcomes
of the UPR may be exploited as therapeutic tools to treat cancer.
2015 Elsevier Ltd. All rights reserved.

1. Introduction
The main functions of the endoplasmic reticulum (ER) include
protein folding and maturation, and the maintenance of lipid
and cellular Ca2+ homeostasis [1,2]. If ER protein homeostasis is
disturbed, improperly folded proteins accumulate in the ER, a
condition termed ER stress. This results in the activation of the
unfolded protein response (UPR), an adaptive pathway that aims
to restore ER homeostasis [3]. The UPR is mediated by inositolrequiring enzyme 1 (IRE1), activating transcription factor 6 (ATF6f),
and protein kinase RNA-like ER kinase (PERK), three ER membrane
localized stress sensing proteins [4]. Upon accumulation of misfolded proteins, glucose regulated protein 78(GRP78) is displaced
from the sensors, thereby prompting their activation [5]. Initially
the UPR acts to restore ER homeostasis by halting protein synthesis,
enhancing protein degradation (ER-associated protein degradation
(ERAD)), upregulating the expression of chaperones and foldases
and expanding the ER membrane [4]. However, if these measures
are ineffective, the UPR becomes pro-apoptotic, although the precise mechanisms underlying this switch remain unclear [6].

Corresponding author at: Apoptosis Research Centre, Biosciences Research

Building, Corrib Village, NUI Galway, Dangan, Galway, Ireland. Tel.: +353 91492440;
fax: +353 91494596.
E-mail address: afshin.samali@nuigalway.ie (A. Samali).
http://dx.doi.org/10.1016/j.semcancer.2015.03.003
1044-579X/ 2015 Elsevier Ltd. All rights reserved.

Upon ER stress, IRE1 monomers juxtapose and transautophosphorylate, producing multimers with functional cytoplasmic endoribonuclease (RNase) domains [7]. The IRE1 RNase
domain unconventionally excises a 26-nucleotide intron from Xbox binding protein 1 (XBP1) mRNA [8] which is then ligated
by RNA 2 ,3 -cyclic phosphate and 5 OH ligase (RTCB) [9]. Spliced
XBP1 (XBP1s) is a pro-survival transcription factor that drives the
homeostatic phase of the UPR [3]. IRE1 also cleaves a variety of
mRNA, miRNA and rRNA transcripts through a process termed regulated IRE1-dependant decay of mRNA (RIDD) [10]. Intriguingly,
RIDD and XBP1 splicing are differently regulated and can lead
to opposite effects on cell fate decisions [11]. IRE1 can also signal through a protein scaffold named the UPRosome [12]. Under
stress conditions the dissociation of GRP78 causes ATF6 to be
exported to the golgi complex [13] where it is cleaved into its
active form, ATF6f, by site 1 and 2 proteases [14]. ATF6f then
translocates to the nucleus where it selectively activates UPR gene
transcription [15]. Following GRP78 dissociation, PERK oligomerizes and trans-autophosphorylates leading to the phosphorylation
the eukaryotic initiation factor 2 (eIF2) at Ser51, thereby attenuating general translation [16]. This also allows the selective
translation of a particular subset of transcripts [17], including
activating transcription factor 4 (ATF4), causing subsequent upregulation of adaptive genes [18]. However, ATF4 also upregulates
C/EBP homology protein (CHOP), a pro-death transcription factor
[19] (Figs. 1 and 2).

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M. Maurel et al. / Seminars in Cancer Biology 33 (2015) 5766

Fig. 1. UPR regulatory mechanisms of adaptive responses to ER stress. Active IRE1 RNase regulates pro-survival response through RIDD and unconventional splicing of
XBP1. The latter induces expression of pro-survival UPR genes including p58IPK , a negative feedback regulator of PERK. IRE1 interaction with HSP72, BAX and BAK enhances
XBP1s signaling. PERK phosphorylates NRF2 to induce expression of antioxidant and detoxifying enzymes, and eIF2 to turn off global protein synthesis. ATF4 is selectively
expressed and regulates transcription of pro-survival genes. In addition ATF4 increases miR-211 levels to inhibit CHOP expression. Golgi-translocated and cleaved ATF6
(ATF6f) upregulates XBP1u and targets genes to reduce ER stress independently or in cooperation with XBP1s.

Subversion of the cell fate machinery underlies many of the

hallmarks of cancer [20], so it comes as little surprise that the UPR
plays a pivotal role in malignant transformation, from oncogenesis
to tumor progression and metastasis. Indeed, the oncogeneinduced rapid proliferation of cancer cells requires enhanced
production of membrane and secretory proteins which increases
the demand on the cellular protein folding machinery. Moreover,
the tumor microenvironment is characterized by physiological
stresses such as hypoglycemia, oxidative stress, and hypoxia that
lead to unremitting ER stress and a constantly activated UPR. In
normal cells this stress level would tip the balance in favor of a
pro-apoptotic UPR response with cell death as the outcome. However, cancer cells have an enhanced capacity to resist cell death
thus allowing them to selectively benet from the pro-survival
effects of the UPR [2]. Approaches to therapeutically target the UPR
by inhibiting UPR regulated survival pathways and/or increasing

pro-death signaling in order to tip the balance toward cell death

have attracted a lot of attention in the past few years. However, the
paradox that UPR signaling can lead to both cell survival and cell
death is a distinct challenge for targeting the UPR as an anti-cancer
strategy. To add further complexity, each arm of the UPR has both
pro-death and pro-survival potential. For example, UPR mediated
phosphorylation of eIf2 inhibits its translational activity thereby
reducing the protein load in the ER and is therefore considered
cytoprotective; however prolonged phosphorylation of eIf2
induces cell death. To circumvent this paradox a comprehensive
knowledge of UPR signaling, and how it pertains to a particular
disease state is essential. Here we review our current understanding of pro-survival and pro-death UPR signaling in the context
of their involvement in cancer development and progression and
evaluate how this integrated signaling pathway could be used as
a therapeutic target to reduce or prevent tumor growth.

M. Maurel et al. / Seminars in Cancer Biology 33 (2015) 5766

59

Fig. 2. UPR regulatory mechanisms of pro-apoptotic responses to ER stress. Formation of IRE1 kinaseTRAF2 complex leads to NFB and JNK activation. Both proteins
regulate activity of pro- and anti-apoptotic BCL-2 proteins by transcriptional regulation and phosphorylation, respectively. Higher order oligomerization of IRE1 increases
RIDD activity inducing the degradation of pro-survival mRNA substrates. Binding of BI-1 to IRE1 inhibits XBP1s pro-survival response. BI-1 also inhibits cleavage of ATF6 and
therefore blocks the downstream signaling pathway. CHOP, whose induction strongly depends on ATF4, regulates synthesis of proteins involved in cell fate decisions. GADD34
in complex with PP1 enhances protein synthesis through dephosphorylation of eIF2 and induces protein overloading in ER lumen. ATF4 together with NRF2 downregulates
miR-106b-25 and potentiates Bim gene expression.

2. Targeting the UPR sensors

2.1. Modulation of IRE1 signaling
IRE1 produces either adaptive or death signals through its
RNase activity [12]. This occurs through both the unconventional
splicing of XBP1 mRNA and through RIDD. Whereas XBP1 mRNA
splicing is cytoprotective, RIDD can either preserve ER homeostasis or induce cell death [10]. Hence, modulators of both RNase
activities might represent potentially attractive targets for cancer therapeutics. To date, the identication of IRE1 inhibitors
has mainly focused on their capacity to inhibit the splicing of
XBP1 mRNA. Thus far IRE1 inhibitors interact either with the
catalytic core of the RNase domain or with the nucleotide binding pocket within the kinase domain (Table 1). MKC-3946 [21],
3-methoxy-6-bromosalicylaldehyde [22], 48C [23], STF-083010

[24] and toyocamycin [25] are hydrophobic inhibitors of IRE1

RNase (Table 1). They have similar structures containing a common aldehyde moiety that operates by formation of a Schiff base
with IRE1 K907, a key residue within the hydrophobic pocket of
the IRE1 RNase catalytic site [26]. This covalent bond impedes
substrate binding and catalysis without affecting the phosphorylation and the oligomerization of IRE1 [26]. Moreover, the
trans-autophosphorylation of IRE1 induces an allosteric change and
stabilizes an active conformation that is characterized by the spatial positioning of the aspartic acid-phenylalanine-glycine (DGF)
motif at the base of the kinase activation loop, deep within the
nucleotide binding pocket between the N-terminal kinase lobe
containing nucleotide binding residues and the C-terminal lobe
containing the activation loop [27]. Type I IRE1 kinase inhibitors,
such as APY29 [27] and sunitinib [28], target the ATP binding site,
inhibit the phosphorylation but stabilize an active conformation of

Activation
Activation
Activation
Inhibition
Activation
[30]
Inhibition
Inhibition
Inhibition
Inhibition
Activation
[31]
Inhibition
Inhibition
Inhibition
ND
ND
[31]
Inhibition
Activation
Activation
ND
ND
[28]

Compound 3
APY29

Inhibition
Activation
Activation
ND
ND
[29]

Sunitinib

Type II
Type I

Not effective
Not effective
Inhibition
ND
Inhibition
[24]
Not effective
Not effective
Inhibition
ND
Inhibition
[21]

Not effective
Not effective
Inhibition
ND
Inhibition
[25]

STF083010
MKC-3946

Not effective
Not effective
Inhibition
Inhibition
ND
[22]
Not effective
Not effective
Inhibition
Inhibition
Not effective
[23]
IRE1 phosphorylation
IRE1 oligomerization
XBP1 mRNA splicing
RIDD
Survival
References

Structure

48C
Molecule

3-Methoxy-6bromosalicyl-aldehyde

Catalytic core of the RNase domain

Target

Table 1
Modulators of IRE1 activity.

Toyocamycin

ATP binding pocket of the kinase domain

KIRA6

FIRE

AHGKIKAMIEDFGLCKKL

M. Maurel et al. / Seminars in Cancer Biology 33 (2015) 5766

Kinase domain

60

the kinase catalytic domain (Table 1) [29]. These molecules stabilize the oligomeric status of IRE1 and the splicing of XBP1 mRNA.
Similarly, an articial peptide derived from the nucleotide-binding
domain of IRE1, promotes IRE1 oligomerization and XBP1 mRNA
splicing while inhibiting RIDD [30]. In contrast, type II IRE1 kinase
inhibitors, such as compound 3 and KIRA6, selectively stabilize
an inactive conformation of the nucleotide binding site that is
characterized by the outward movement of DGF, named DGF out
conformation [31] (Table 1). These molecules inhibit XBP1 mRNA
splicing by disrupting IRE1 oligomers. Moreover, protein disulde
isomerase (PDI) family A, member 6 controls the duration of XBP1
mRNA splicing by direct binding to IRE1 C148 leading to the modulation of signaling oligomers [32,33].

2.2. Modulation of PERK/eIF2 signaling

Activation of the PERK pathway can lead to opposite effects
on cell viability [34]. Currently, two anticancer strategies targeting PERK/eIF2 signaling were proposed that are based either on
eIF2 phosphorylation inhibition or on its prolonged phosphorylation (Table 2). PERK inhibitors GSK2606414 [35] and GSK2656157
[36] are ATP competitive inhibitors. PERK kinase inhibition impedes
the subsequent phosphorylation of eIF2 upon ER stress. Inhibition of eIF2 phosphorylation prevents the reduction of ER protein
load, which in turn reduces adaptation to ER stress and leads to
cell death. Both inhibitors were described to signicantly reduce
tumor growth in mouse xenograft models [37]. Moreover, the
integrated stress response inhibitor (ISRIB) has also been identied as a new PERK signaling inhibitor [38]. Interestingly, ISRIB
does not inhibit PERK or eIF2 phosphorylation but rather blocks
downstream events and reverses the effects of eIF2 phosphorylation through an as yet unknown mechanism. Notably, ISRIB
treatment only affects the survival of cells under ER stress [38].
In this context, eIF2 phosphorylation is a cytoprotective cellular
process. In contrast, both salubrinal and guanabenz were shown
to target the growth arrest and DNA-damage-inducible protein
34 (GADD34)/protein phosphatase 1c (PP1c) complex, inhibiting
eIF2 dephosphorylation thereby leading to cell death [39,40].
It has been proposed that prolonged phosphorylation of eIF2
enhances TNF-related apoptosis-inducing ligand (TRAIL)-induced
apoptosis and reduces Rac1 GTPase activity, thus impacting on cancer cells sensitivity to TRAIL-induced cell death [39,40].

2.3. Modulation of ATF6 signaling

Activation of ATF6 depends on the dissociation from GRP78
but also on a redox process involving PDIs [41]. Numerous PDI
inhibitors have been described in the literature, such as PACMA31
[42], RB-11-ca [43], P1 [44] and 16F16 [45] (Table 3). These
molecules possess an electrophilic moiety that reacts covalently
with the cysteine residues within the PDI thioredoxin domain. As
such they block the disulde exchange capacity of those enzymes
and impact on tumor growth through the irreversible inhibition of
PDI activity. In addition to their impact on protein folding, some
PDIs act as upstream regulators of important UPR stress sensors.
Indeed PDI family A, member 5 (PDIA5) regulates ER stress-induced
ATF6 activation through disulde bond rearrangement, thus blocking ATF6 export from the ER to the golgi complex (GC), thereby
preventing its activation and the subsequent transactivation of its
target genes [45]. Another way to prevent ATF6 activation is to block
the proteases S1P and S2P in the GC using AEBSF [46] (Table 3).
Although no specic inhibitor of ATF6 activation has been discovered yet, efforts are being made to identify such molecules with
promising therapeutic applications.

Table 2
Modulators of PERK activity.
Target

ATP binding pocket of the kinase domain

ND

GADD34/PP1

Molecule

GSK2606414

GSK2656157

ISRIB

Salubrinal

Guanabenz

Inhibition
Inhibition
Inhibition
Inhibition
Inhibition
[35]

Inhibition
Inhibition
Inhibition
Inhibition
Inhibition
[36]

Not effective
Not effective
Inhibition
Inhibition
Inhibition
[38]

Not effective
Prolonged
Activation
Activation
Inhibition
[39]

Not effective
Prolonged
Activation
Activation
Inhibition
[40]

Structure

Table 3
Inhibitors of ATF6 pathway.
Target

PDI inhibitors: thioredoxin domain

Molecule

PACMA31

RB11-ca

P1

16F16

Serine protease inhibitor

AEBSF

[42]

[43]

[44]

[47]

[46]

M. Maurel et al. / Seminars in Cancer Biology 33 (2015) 5766

PERK phosphorylation
eIF2 phosphorylation
ATF4 expression
CHOP expression
Survival
References

Structure

References

61

62

M. Maurel et al. / Seminars in Cancer Biology 33 (2015) 5766

2.4. Targeting the UPR as an adjuvant therapy

Many drugs used for cancer therapy have been described to activate the UPR. Therefore combining these drugs with a molecule that
exacerbates ER stress could synergize to induce cancer cells death.
UPR activation has been shown to contribute to drug resistance;
therefore preventing the UPR could re-sensitize cancer cells to therapies [47]. There are many examples in the literature that illustrate
the improved efciency of combined therapies. For example, salubrinal or doxorubicin combined with bortezomib increases cancer
cell death in hepatoma and diffuse large B cell lymphoma, respectively [40,48]. Moreover, toyocamycin can overcome bortezomib
resistance in multiple myeloma [25,49]. Another good example
of adjuvant therapy has been recently reported in leukemia cells
where 16F16 resensitizes tumor cells to imatinib [45].

3. The IRE1 pathway

3.1. Pro-survival and pro-death IRE1 signals
IRE1 signaling can induce opposite effects on cell fate through
(i) the unconventional splicing of XBP1 mRNA, (ii) RIDD, (iii) formation of the UPRosome and (iv) post-translational modications.
The splicing of XBP1 mRNA yields an active transcription factor
that activates a cytoprotective response through the transcription
of genes involved in ERAD, protein folding, glycosylation and trafcking to match the folding demand [50]. Moreover, IRE1 exhibits
a basal RIDD activity required to maintain ER homeostasis [10].
RIDD may regulate ER homeostasis by reducing the load of ER client
proteins through mRNA degradation thereby decreasing the total
protein inux into the ER [51]. The decay of specic RIDD substrates
required for gene expression may contribute to the global inhibition of protein synthesis [10,52]. The mechanisms involved in the
apoptotic switch driven by IRE1 remain controversial. RIDD activity increases proportionally with ER stress intensity inducing the
degradation of mRNA substrates required for cell survival and cell
growth thus leading to cell death [10] (Fig. 1). Indeed, RIDD induces
the decay of several miRNA precursors, such as premiR-17 [53].
MiR-17 represses the expression of the pro-oxidant thioredoxininteracting protein (TXNIP) that contributes to the activation of
the NLR family pyrin domain containing 3 (NLRP3) inammasome
[54]. The decay of premiR-17 by RIDD increases TXNIP expression,
NLRP3 inammasome activation and the subsequent cleavage of
pro-caspase-1 and interleukin-1 secretion, thereby inducing systemic or local inammatory responses and promoting cell death
[54].
The composition of the UPRosome depends on ER stress intensity and modulates IRE1 signaling [12]. The interaction of BCL-2
associated X-protein (BAX) and BCL-2 antagonist/killer 1 (BAK)
with the cytosolic domain of IRE1 is essential to induce XBP1
splicing [55]. In addition, p53 upregulated modulator of apoptosis
(PUMA) and BCL-2-interacting mediator of cell death (BIM) interact
with IRE1 to maintain a sustained XBP1 mRNA splicing [56]. BAX
inhibitor 1 (BI-1) can compete with BAX/BAK for binding to IRE1
thereby inhibiting XBP1 splicing and survival following ER stress
[55]. Upon irreversible ER stress, reticular BAK, in response to BIM
and PUMA, induces cytochrome c release by a mechanism dependent on calcium release and an IRE1TNF receptor-associated
factor 2 (TRAF2) interaction, revealing a communication pathway
between the ER and mitochondria to trigger cell death [57]. In
response to ER stress, TRAF2 is recruited at the ER membrane
and forms a protein complex with the cytosolic domain of IRE1
and phosphorylated apoptosis signal-regulating kinase 1 (ASK1).
The IRE1/TRAF2/ASK1 complex leads to the activation of c-Jun Nterminal kinase (JNK) that phosphorylates (i) B-cell lymphoma

2 (BCL-2) and BCL-extra-large (BCL-XL ) counteracting their antiapoptotic functions and (ii) BIM and BH3 interacting-domain death
agonist (BID) enhancing their pro-apoptotic activities [5759]
(Fig. 2). Another component of the UPRosome, heat shock protein
(HSP) 72 also binds to IRE1 to enhance XBP1s production and to
protect against ER stress-induced apoptosis [60]. However, HSP90
and the co-chaperone cell division cycle 37, inhibit IRE1 transautophosphorylation and oligomerization [61].
IRE1 activity can also be controlled by post-translational
modications, such as phosphorylation, ADP-ribosylation and
ubiquitination. IRE1 phosphorylation in the activation loop is
important for the activation of its RNase activity [62]. Han et al.
have shown that XBP1 mRNA splicing and RIDD activities can
be uncoupled and suggest that the cytoprotective effect of IRE1
requires only pseudokinase activation and XBP1 splicing, whereas
apoptosis needs phosphotransfer activation and is RIDD dependent
[11]. A more recent study suggests that distinct IRE1 oligomerization states regulate XBP1 splicing and RIDD. IRE1 dimerization
would be sufcient to induce RIDD whereas XBP1 splicing requires
higher order oligomers [63]. Moreover, IRE1 is ADP-ribosylated
and activated by poly (ADP-ribose) polymerase 16 (PARP16), a
tail-anchored ER transmembrane protein that is upregulated during ER stress. Cells that lack PARP16 are highly sensitive to ER
stress, resulting in an increased level of cell death [64]. A recent
publication reported that the ubiquitination of IRE1 by the HSC70interacting protein CHIP is required for IRE1/TRAF2/JNK signaling
[65].

3.2. Directing IRE1 signaling toward cell death in cancer

Cancer cells favor pro-survival IRE1 signaling to survive oncogene expression or harsh conditions. Elevated XBP1s levels are
observed in a number of tumors and correlate with poor prognosis [66,67]. XBP1 splicing is essential for cancer cell survival
under hypoxic conditions [68]. In contrast, the role of RIDD remains
unclear. Depending on the context, it plays either anti- or prooncogenic roles. In glioblastoma, RIDD enhances collective cell
migration by down-regulating SPARC mRNA expression [69]. RIDD
also reduces Period1 mRNA expression thereby disrupting the circadian clock and activating pro-inammatory mechanisms [70]. In
hepatoma cells, miR-1291 targets IRE1 leading to the overexpression of the pro-oncogenic glypican-3 [71], another RIDD substrate.
However, because of the lack of experimental data, it is difcult
to predict what the physiological effect of IRE1 inhibitors on cancer cells will be. The description of the effects mediated by these
compounds is incomplete and often controversial. For instance,
STF-083010 and toyocamycin have been described to inhibit the
splicing of XBP1 mRNA and to decrease tumor growth [21,24,25].
However their effects on RIDD have not been tested. In contrast,
MKC-3946, 3-methoxy-6-bromosalicylaldehyde, and 48C impede
XBP1 mRNA splicing as well as RIDD [22,23]. The effect of 3methoxy-6-bromosalicylaldehyde has not yet been evaluated in
cultured cells or in vivo. Interestingly, 48C does not affect the survival of cells under acute ER stress, but reduces the expansion of
the secretory capacity [23]. For most of the inhibitors, the effects
on cell survival or RIDD have not been tested yet. However, KIRA6
increases cell survival by inhibiting both XBP1 mRNA splicing and
RIDD whereas FIRE increases cell survival by inducing XBP1 mRNA
splicing and decreasing RIDD [30,31]. Overall, these ndings raise
the possibility that IRE1 inhibitors can trigger different IRE1 outputs, highlighting the necessity to systematically test their effects
on cell survival and to screen for new inhibitors able to uncouple
XBP1 mRNA splicing and RIDD. As such, RTCB could represent a relevant target to reduce splicing and maintain RIDD activity. It would
be interesting to identify whether selective activation of RIDD can

M. Maurel et al. / Seminars in Cancer Biology 33 (2015) 5766

sensitize cancer cells to chemotherapy. Moreover, perturbing the

UPRosome could also be of interest.

63

miR-211 expression which attenuates CHOP expression, thus providing evidence that a PERKATF4-dependent miR-211 functions
as a key regulator of PERK-dependent pro-survival signals [85]
(Fig. 1).

4. The PERK pathway

4.1. Pro-death and pro-survival PERK signals
PERK signaling typies the ER stress response in that it possesses an early adaptive phase and a delayed pro-death modality.
Classically the PERK/eIF2/ATF4 axis is capable mediating both
outcomes, though the precise mechanism for how PERK signaling
transitions from being pro-survival to pro-death is still unknown.
Pro-death signaling through PERK might primarily be mediated
through CHOP, a transcriptional target of ATF4 [19]. CHOP expression increases during ER stress and persists until cell death [72].
CHOP promotes apoptosis by downregulating anti-apoptotic BCL2 and induced myeloid leukemia cell differentiation protein (MCL1)
and up-regulating pro-apoptotic BIM, BCL-XL and BAX [73]. CHOP
can also promote the expression of caspase-3 and GADD34 which,
when associated with the PP1 catalytic subunit dephosphorylates
eIF2, thereby restoring global protein translation. In addition,
CHOP increases the expression of the oxidoreductase endoplasmic oxidoreductin 1 (ERO1) which generates reactive oxygen
species (ROS) and activates the ER calcium channel inositol 1,4,5triphosphate receptor [73]. The leakage of ROS and of calcium
into the cytosol triggers apoptosis (Fig. 2). PERK is required for
the proper maintenance of mitochondriaER contact sites. This
connection is required for proper ROS signaling and ultimately apoptosis [74]. A recent report demonstrated that ER stress-induced
apoptosis is controlled by death receptor 5 (DR5) and that DR5
levels are regulated by the opposing activities of PERK and IRE1.
PERKCHOP activity induces DR5 transcription, whereas IRE1 promotes DR5 mRNA decay [75]. The cumulative effect of CHOP and
ATF4 has been shown to induce increased protein production and
cell death [76]. PERK has also been shown to promote death independently of CHOP by activating ATF4, which in turn inhibits the
expression of miR-106b-25, increasing BIM expression and leading to cell death [77] (Fig. 2). MiR-30c-2*, which is induced by
PERK, has been shown to limit the expression of the pro-adaptive
factor XBP1s which thus inuences cell fate [78]. However, no
involvement of miR30c-2* in cancer has been reported to date.
To promote survival, PERK phosphorylates eIF2 on Ser51 causing translation attenuation thereby preventing protein overload in
the ER [16]. Consequentially, levels of short-lived proteins such as
cyclin D1 (CCND1) are rapidly depleted. Inhibition of CCND1 synthesis results in cell cycle arrest in G1 phase thus giving cells time to
recover and resume normal function [79]. Despite phosphorylation
of eIF2 halting global translation, a subset of mRNA transcripts,
including ATF4, are selectively translated. ATF4 promotes expression of pro-survival genes involved in the oxidative stress response,
amino acid metabolism and protein folding [80,81] (Fig. 1). Nuclear
factor (erythroid-derived 2)-like 2 (NRF2) is another direct target
of PERK mediated phosphorylation. Once phosphorylated, NRF2 is
released from inhibitory interaction with Kelch-like ECH associated
protein 1 (KEAP1) and translocates to nucleus to regulate genes
encoding antioxidant and detoxifying enzymes (NAD(P)H dehydrogenase quinone 1, NQO1; heme oxygenase 1, HO-1; glutathione
S-transferase, GST; superoxide dismutase, SOD1), thus restoring
redox homeostasis [82] (Fig. 1). PERK also induces expression of
cIAPs (cellular inhibitor of apoptosis proteins), factors that promote cell survival and are well known to contribute to oncogenesis
[83]. This suggests that cIAPs might act in a negative feedback
loop leading to inhibition of PERK-dependent pro-apoptotic signaling. However, if PERK signaling persists it downregulates cIAPs
in parallel with CHOP induction [84]. Finally, PERK also controls

4.2. PERK signaling in cancer

PERK-regulated pathways are important for cancer cell survival,
as cells with compromised PERK, ATF4 or NRF2 signaling are more
sensitive to ER stress [82]. Higher levels of ATF4 have been observed
in malignant tissues obtained from various cancer patients [86]. In
particular, ATF4 has been reported to be specically upregulated
in hypoxic regions of tumors and the PERKeIF2ATF4 axis is
reported to help tumor cells to survive hypoxia and detachment
from the extracellular matrix through the induction of autophagy,
and in the latter case, inhibition of mechanistic target of rapamycin
complex 1 (mTORC1) [87,88]. Additionally, MYC-induced tumorigenesis is dependent on PERK-mediated autophagy, as inhibition
of PERK signaling reduces MYC driven tumor formation. Peculiarly,
this mode of PERK signaling does not occur during ER stress, suggesting that there may be ER stress independent roles for PERK
in promoting cancer. Indeed, in the absence of ER stress PERK has
been shown to play a role in vascular endothelial growth factor
(VEGF) signaling, which drives tumor angiogenesis [89]. Tumors
from K-Ras-transformed MEFs derived from perk/ mice have signicantly reduced growth and angiogenesis in xenograft models
[90]. PERK signaling has been implicated in the resistance to external stressors and to certain therapies [91,92]. However, there are
numerous reports that implicate CHOP in potentiating cell death
in response to a variety of treatments [9395]. This inconsistency
poses a problem when we consider PERK as a potential therapeutic
target. Inhibiting PERK signaling may stop pro-survival autophagy,
but it may also inhibit a major stress-induced death effector CHOP.
Thus, certain cancers in which ATF4 provides a survival advantage, may not necessarily respond to PERK inhibition. Increased
knowledge of these mechanisms could lead to the development of
strategies to inhibit the pro-survival potential of ATF4 while leaving
its ability to induce CHOP intact. Failing this, improved classication of downstream pro-survival ATF4 genetic targets could lead to
the identication of more specic drug targets with reduced side
effects.

5. The ATF6 pathway

5.1. Pro-death and pro-survival ATF6 signals
ATF6f is a transcription factor which, like the two other UPR sensors, can play pro-survival or pro-death roles. ATF6f mediates the
adaptive UPR response by up-regulation of genes mainly encoding chaperones (GRP78, GRP94, HYOU1), protein folding enzymes
(PDI, 13 kDa FK506 binding protein), proteins involved in quality
control and ERAD [15,96] (Fig. 1). ATF6f can modulate gene expression independently or in co-operation with XBP1s. As such it has
been found to decrease amyloidogenic Ig light chain (LC) secretion
by remodeling the endoplasmic reticulum proteostasis network.
Stress-independent activation ATF6f also attenuates extracellular
aggregation of amyloidogenic LC into soluble aggregates [97]. In
contrast overexpression of ATF6f in myoblast cells induces apoptosis and results in the up-regulation of WW domain binding protein 1
(WBP1). ATF6f/WBP1 signaling was shown to selectively downregulate MCL-1, an anti-apoptotic BCL-2 family member. Thus ATF6f
has pro-apoptotic potential through the down-regulation of MCL-1
in myoblasts [98].

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M. Maurel et al. / Seminars in Cancer Biology 33 (2015) 5766

5.2. ATF6 signaling in cancer

Studies on the role of ATF6 in cancer are very limited. It has
been reported that ATF6f is essential for the adaptation of dormant
but not proliferating squamous carcinoma cells to chemotherapy,
nutritional stress and in vivo tumor environment [99]. The underlying pro-survival mechanism involves the induction of Ras homolog
enriched in brain (Rheb) and mTOR activation [99]. It has been proposed that ATF6f might play a critical role in hepatocarcinogenesis
[100,101]. ATF6f up-regulates unspliced XBP1 (XBP1u), which is
the major substrate for IRE1 RNase [8] (Fig. 1). It is accepted that
XBP1u is rapidly degraded by the proteasome and does not play
a role in regulating the cellular response to ER stress. However,
XBP1u plays an important role in autophagy and survival in human
colon cancer [102]. Other studies suggest that XBP1u can act as a
negative feedback regulator of the UPR by inhibiting the expression
of XBP1s target genes and enhancing ATF6f and XBP1s degradation by the proteasome upon prolonged ER stress [102,103]. In
addition to dissociation from GRP78, redox reactions and glycosylation are involved in ATF6 activation upon ER stress [41,104].
Recently, PDIA5 has been identied as key regulator of ATF6 activation upon ER stress and a new potential therapeutic target in cancer.
Importantly, PDIA5-mediated ATF6 activation may contribute to
the resistance of leukemia cells to imatinib [45]. Thus, it would be
of great interest to determine the potential of PDIs to modulate
ATF6 activity.

6. Concluding remarks
Most normal cells maintain their UPR in an inactive state under
basal conditions, only activating it transiently when facing physiological challenges that induce ER stress [1,47]. In contrast cancer
cells often display constitutive activation of pro-adaptive UPR
signaling, meanwhile tuning down pro-death UPR signals. This
observation not only reects the selection process tumor cells have
undergone, but is also relevant to conditions that enable cancer
cells to survive deleterious effects of the microenvironment. The
constitutive activation of basal UPR also allows the tumor to grow,
become vascularized and to acquire resistance to chemotherapeutic agents [47]. Hence, targeting the UPR in cancer represents an
appealing strategy that could selectively affect cancer cells and
spare normal cells. The current strategies developed so far aim
at switching pro-survival UPR signals into pro-death UPR either
through the inhibition of pro-survival UPR components or through
the induction of exacerbated ER stress [47] or, a combination of
both. Consequently, cancer cells exposed to excessive/unresolvable
levels of ER stress are therefore driven toward death pathways.
In the past decade, many studies have documented the different mechanisms involved in UPR signaling output modulation,
thus underlining that this pathway is nely controlled at numerous
levels including transcriptional, post-transcriptional, translational
and post-translational. Nevertheless, the relevance of some of
these regulatory mechanisms has never been tested in cancer (e.g.,
systematic analysis of CHOP expression or RTCB expression and
activity, RIDD activity modulation and composition of the UPRosome). This is reected by recent ndings that demonstrated that
the sensitivity/resistance of tumors to specic drugs could be predicted based on the expression of UPR markers such as XBP1s,
GRP78 or ATF6. Therefore, there is a unique opportunity to establish and validate new tumor classications based on UPR activation
markers and provide a more personalized UPR-based typing of the
tumors. This could be of great use not only for determining the therapy to be used to treat a particular tumor type but also to select
the most appropriate UPR modulators as neo-adjuvant therapies.
Indeed, opposing strategies and effects on cell survival have been

described with the current IRE1 and PERK inhibitors [47]. As such,
better understanding of the UPR and, in particular, its subversion
by cancer cells in a variety of contexts would facilitate the selection of the most appropriate, efcient and personalized treatment
for each type of tumor.

Conict of interest
The authors declare no conict of interest.

Acknowledgments
This publication has emanated from research conducted with
the nancial support of Irish Research Council Grants Nos,
RCS1350 & RCS999, Science Foundation Ireland under Grant No.
06/RFP/BIC002, by Belgian Grant Interuniversity Attraction Poles,
IAP 7/32; and by grants from Institut National du Cancer (INCa) and
Ligue Contre le Cancer to EC.

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