Controlling the unfolded protein response-mediated life and death decisions in cancer.

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Contents lists available at ScienceDirect

Seminars in Cancer Biology journal homepage: www.elsevier.com/locate/semcancer

Review

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Controlling the unfolded protein response-mediated life and death decisions in cancer

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a

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Marion Maurel a,d , Eoghan P. McGrath a , Katarzyna Mnich a , Sandra Healy a , Eric Chevet b,c,d , Afshin Samali a,∗

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Apoptosis Research Centre, National University of Ireland, Galway, Ireland Inserm U1053, F-33000 Bordeaux, France c University of Bordeaux, F-33000 Bordeaux, France d Centre de Lutte Contre le Cancer Eugène Marquis, 35000 Rennes, France b

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a r t i c l e

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a b s t r a c t

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Keywords: Apoptosis Cancer Cell death ER stress UPR

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1. Introduction

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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 Published by Elsevier Ltd.

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 at restoring 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 (GRP) 78 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

∗ 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: [email protected] (A. Samali).

are ineffective, the UPR becomes pro-apoptotic, although the precise mechanisms underlying this switch remain unclear [6]. 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 X-box 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 transautophosphorylates 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 the activating transcription factor 4 (ATF4), causing subsequent upregulation of adaptive genes

http://dx.doi.org/10.1016/j.semcancer.2015.03.003 1044-579X/© 2015 Published by Elsevier Ltd.

Please cite this article in press as: Maurel M, et al. Controlling the unfolded protein response-mediated life and death decisions in cancer. Semin Cancer Biol (2015), http://dx.doi.org/10.1016/j.semcancer.2015.03.003

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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 UPR pro-survival 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) activates XBP1u and targets genes to inhibit ER stress independently or in cooperation with XBP1s.

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[18]. However, ATF4 also upregulates C/EBP homology protein (CHOP), a pro-death transcription factor [19] (Figs. 1 and 2). 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 oncogene-induced 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 proapoptotic UPR response with cell death as the outcome. However, cancer cells have an enhanced capacity to resist cell death thus allowing them to selectively benefit from the pro-survival effects of the UPR [2]. Approaches to therapeutically target the UPR by

inhibiting UPR regulated survival pathways and/or increasing prodeath 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 prodeath 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.


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Fig. 2. UPR regulatory mechanisms of pro-apoptotic responses to ER stress. Formation of IRE1␣ kinase–TRAF2 complex leads to NF␬B 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.

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2.1. Modulation of IRE1 signaling

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IRE1 produces either adaptive or death signals through its RNase activity [12]. This occurs through both the unconventional splicing of XBP1 mRNA and the 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 identification 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], 4␮8C [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


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Inhibition Inhibition Inhibition Inhibition Activation [31] Inhibition Inhibition Inhibition ND ND [31] Inhibition Activation Activation ND ND [28] Inhibition Activation Activation ND ND [29]

APY29

Not effective Not effective Inhibition ND Inhibition [25] Not effective Not effective Inhibition ND Inhibition [24] Not effective Not effective Inhibition ND Inhibition [21] Not effective Not effective Inhibition Inhibition ND [22] Not effective Not effective Inhibition Inhibition Not effective [23] Structure

IRE1 phosphorylation IRE1 oligomerization XBP1 mRNA splicing RIDD Survival References

FIRE KIRA6 Compound 3 Sunitinib

Type II Type I

ATP binding pocket of the kinase domain

Toyocamycin STF083010 MKC-3946 3-Methoxy-6bromosalicyl-aldehyde

Catalytic core of the RNase domain

4␮8C Molecule

Target

Table 1 Modulators of IRE1 activity.

Activation Activation Activation Inhibition Activation [30]

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the kinase catalytic domain (Table 1) [29]. These molecules stabilize the oligomeric status of IRE1 and the splicing of XBP1 mRNA. Similarly, an artificial 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 disulfide 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 significantly reduce tumor growth in mouse xenograft models [37]. Moreover, the integrated stress response inhibitor (ISRIB) has also been identified 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 disulfide 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 disulfide 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 specific inhibitor of ATF6 activation has been discovered yet, efforts are being made to identify such molecules with promising therapeutic applications.


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Not effective Prolonged Activation Activation Inhibition [40]

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Table 3 Inhibitors of ATF6 pathway. Target

PDI inhibitors: thioredoxin domain

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[43]

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Table 2 Modulators of PERK activity.

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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 efficiency 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].

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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 modifications. 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 trafficking 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 influx into the ER [51]. The decay of specific 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) inflammasome [54]. The decay of premiR-17 by RIDD increases TXNIP expression, NLRP3 inflammasome activation and the subsequent cleavage of pro-caspase-1 and interleukin-1␤ secretion, thereby inducing systemic or local inflammatory 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 therefore 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 IRE1–TNF 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 [57–59] (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 modifications, 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 sufficient 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-inflammatory 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 difficult 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 4␮8C 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, 4␮8C 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 findings 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


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in parallel with CHOP induction [84]. Finally, PERK also controls miR-211 expression which attenuates CHOP expression, thus providing evidence that a PERK–ATF4-dependent miR-211 functions as a key regulator of PERK-dependent pro-survival signals [85] (Fig. 1).

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PERK signaling typifies 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 antiapoptotic BCL-2 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 growth arrest and DNA-damage-inducible protein 34 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 1,4,5-triphosphate receptor [73]. The leakage of ROS and of calcium into the cytosol triggers apoptosis (Fig. 2). PERK is required for the proper maintenance of mitochondria–ER 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␣. PERK–CHOP 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 pro-adaptive factor XBP1s which thus influences 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

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 specifically upregulated in hypoxic regions of tumors and the PERK–eIF2␣–ATF4 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 significantly 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 [93–95]. 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 classification of downstream pro-survival ATF4 genetic targets could lead to the identification of more specific drug targets with reduced side effects.

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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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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 identified 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 reflects 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 finely 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 reflected by recent findings that demonstrated that the sensitivity/resistance of tumors to specific 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 classifications 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

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Controlling caspase activity in life and death.

The complexity of life and death decisions in mitosis.

Understanding life and death decisions in human leukaemias.

Prostate cancer and the unfolded protein response.

Celastrol induces unfolded protein response-dependent cell death in head and neck cancer.

Mitochondrial oxidative phosphorylation controls cancer cell's life and death decisions upon exposure to MAPK inhibitors.

Multiple Mechanisms of Unfolded Protein Response-Induced Cell Death.

Targeting unfolded protein response in cancer and diabetes.

death decisions for the neurologically impaired.

The unfolded protein response as a target for cancer therapy.

Endoplasmic Reticulum Stress, Unfolded Protein Response, and Cancer Cell Fate.

Controlling Directed Protein Interaction Networks in Cancer.

Unpacking the unfolded protein response.

Targeting the unfolded protein response, XBP1, and the NLRP3 inflammasome in fibrosis and cancer.

Death Decisions by Tumor Cells with Potential Clinical Applications.

Melanoma and the Unfolded Protein Response.

The unfolded protein response and diabetic retinopathy.

The unfolded protein response in multiple sclerosis.

The unfolded protein response in virus infections.

Molecular pathways: the PERKs and pitfalls of targeting the unfolded protein response in cancer.

MYC regulates the unfolded protein response and glucose and glutamine uptake in endocrine resistant breast cancer.

Ribosomal protein L19 overexpression activates the unfolded protein response and sensitizes MCF7 breast cancer cells to endoplasmic reticulum stress-induced cell death.

Future Tense and Economic Decisions: Controlling for Cultural Evolution.

Borrelidin Induces the Unfolded Protein Response in Oral Cancer Cells and Chop-Dependent Apoptosis.