Reprogramming of Molecular Switching Events in ...

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REVIEW ARTICLE

Reprogramming of Molecular Switching Events in UPR Driven ER Stress: Scope for Development of Anticancer Therapeutics D. Nayaka,b, R. Rasoola,b, S. Chakrabortya,b, B. Raha,b, A. Katocha,b, J. Rasoolc, H. Aminb and A. Goswamia,b,* a

b

Academy of Scientific & Innovative Research (AcSIR), New Delhi, India; Cancer Pharmacology Division, c Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu, J&K - 180001, India; Chemistry Division, Indian Institute of Integrative Medicine (CSIR), Srinagar, J&K, India

ARTICLE HISTORY Received: January 16, 2016 Revised: July 19, 2016 Accepted: August 11, 2016 DOI: 10.2174/1566524016666160 829152658

Abstract: The incitement of unfolded protein response (UPR) during endoplasmic reticulum (ER) stress by diverse intracellular (hypoxia, nutrient deprivation, etc.) or extracellular (environmental or drug induced) stimuli is considered a major threat for perturbing cellular homeostasis leading to the aggregation of unfolded proteins inside the cell. The catastrophic UPR events emerge as a prime cellular adaptation by remodeling cancer cell signaling and restoring ER homeostasis in favor of tumor growth. The transient ER stress protects cancer cells from undergoing apoptosis, whereas the prolonged stress response further activates many cell death A. Goswami pathways. The present review summarizes the UPR mediated triggering of transcriptional and translational reprogramming, which will provide novel therapeutic strategies towards pro-death mechanisms rather than a cellular adaptation in tumorigenesis. Nonetheless, the current topic also points out the reprogramming of emerging molecular switching events by complex UPR-mediated signaling to trigger apoptosis. The novel agents from various natural, semi-synthetic and synthetic sources that target ER stress signaling pathway to modulate selectively the UPR phenomena with preclinical efficacy are outlined. Since major emphasis on ER stress-induced transcriptional and translational reprogramming remains to be explored, we believe that the current subject will instigate more attention from the biomedical researchers in this certain research direction.

Keywords: ER stress, UPR, molecular switching, GRP78, PERK, therapeutic development.

INTRODUCTION The endoplasmic reticulum (ER) is the organelle which optimizes the microenvironment for proteins synthesized de novo to gain their tertiary structures through various post-translational modifications. However, improper protein folding due to various intracellular or extracellular stimuli leads to ER stress. Because of the building up of misfolded protein load in the ER lumen that surpasses ER-associated degradation (ERAD) system which exhibits many additional cellular adaptive pathways to restore ER homeostasis by targeting unfolded proteins towards proteasome-mediated degradation, ultimately initiates a pathologically stressful condition. In such catastrophic condition, eukaryotic cells either limit the translation and over-burden of unfolded proteins or activate the ER resident chaperone proteins mediated ERAD mechanism to reinstate the folding capacity [1]. *Address correspondence to this author at the Cancer Pharmacology Division, Indian Institute of Integrative Medicine (CSIR), Jammu Tawi - 180001, India; Tel: 0191-2569111; Fax: 0191-2569333; E-mail: [email protected] 1566-5240/16 $58.00+.00

However, if the ER stress persists further, cellular machinery finally turns on apoptosis. Recent evidence indicates that several protein kinases regulate ER stress-mediated signaling pathways leading to the pathogenesis of various diseases. Exposure to the toxic chemicals or small molecules severely hampers the protein-folding capability of ER. Such nonphysiological threats crash the UPR mediated adaptive mechanisms, consequently leading to the apoptotic death of a cell. This review focuses on the molecular reprogramming events that take place with the cellular machinery to cope up with the physiological or extracellular stimuli that lead to ER stress conditions. Various targets that mediate the oncogenic signaling processes during the ER-stress and UPR have been described in a precise manner for the drug discovery purposes. Additionally, the small molecules from natural, semisynthetic and synthetic sources that activate reprogramming have been documented for further anticancer therapeutic development.

© 2016 Bentham Science Publishers

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CELLULAR ADAPTATION FOR SURVIVAL IN ER STRESS

From Cellular Adaptation to Autophagy in ER Stress

In cancer, drug discovery targeting to the UPR components has opened multiple avenues and research interests among academia and industries as well. Tumor cells always thrive under the physiological stress conditions like; nutrient deprivation, hypoxia, acidosis etc., inside the tumor microenvironment, thereby depends on a UPR machinery for their survival [2, 3], and by maintaining their invasive behavior by secreting various cytokines and growth factors [4]. However, most normal cells are not exposed to such type of physiological stress conditions and the UPR machinery remains dormant in these cells. Hence, it becomes feasible for researchers to reprogram UPR components to shift the balance of cellular adaptation towards pro-death UPR signals by targeting specific pharmacological agents that may be therapeutically beneficial in cancer therapy.

Autophagy phenomena that act as a double-edged sword in cancer; promotes tumor cell survival and induces the cell death in certain circumstances. It may be considered that autophagy favors the cancer progression at certain points, yet is tumor suppressive at other junctures [12]. Inexplicably, activation of autophagy following ER stress modulates the cell fate that might induce cell survival (protective; [13-16]) or cell death (cytotoxic; [16-21]) depending on the context. The initiation of ER stress might facilitate the induction of autophagy-associated cell death or the stimulation of protective autophagy. Interestingly, this stimulation of protective autophagy following ER stress eventually promotes resistance to certain antitumor therapies [22]. Autophagy alone is not adequate to promote apoptosis. According to a research opinion on roles of autophagy demonstrates that autophagy does not induce apoptosis on its own, rather it is required under certain circumstances along with other pro-death signals to do so. For example, DRAM1 which is stimulated by DNA damage and the tumor suppressor p53 [23, 24] positively regulates autophagy to induce p53 mediated cell death programs. However, when DRAM1 was over-expressed, it altered autophagic signaling to some extent, but could not induce cell death, demonstrating that autophagy is essential, but not adequate to cause apoptosis [23, 25]. Depending upon the intensity and nature of stress (lack of nutrient, hypoxia or treatment with cytotoxic agents) or the cell type (normal versus cancerous), the outcome of autophagy varies. Intriguingly, the rate and extent of autophagy could be altered as a result of diverse intra and extracellular cues to bring about precise consequences. Thus, various factors including the robust ER stress signal, the concomitant activation of associated pathways, the cell type, and so on, should be necessarily coordinated to yield an explicit autophagic response. To overcome chemoresistance, a clear understanding of these processes that occur in cancer cells in response to ER stress is necessary to explore suitable targets leading to therapeutic development. The other way to overcome resistance would likely be the combined inhibition of cellular degradation systems. For example, the coupled inhibition of proteasomal degradation and autophagy could enhance the antitumor efficacy [26]. Targeting proteasomal degradation system has become a suitable strategy for treatment of diverse cancers, and proteasomal inhibitors are known modulators of ER stress signaling cascade [27]. Recently, it was found that ERAD (ER-associated protein degradation) and autophagy were highly impaired due to distortion of balance in the IRE1-XBP1 pathway [28]. Though the ER stress and autophagy are very closely linked consequences of stress condition, it eventually corroborates into a prolong survival potential of cancer cells even after exposure to a higher level of chemotherapy. This purveyance nature of UPR

Induction of UPR Mediated Homeostatic-Apoptotic Switch Ensuring its adaptation strategies, cells have their own machinery to direct the fate of survival/apoptosis during the outcome of ER stress in-vivo. Caspase-12 family of pro-apoptotic proteins associated with the ER membrane, play major roles in ER stress-mediated cell death; but are not activated by other non-ER stimuli. In the pathologic conditions, ER stress triggers cell death by inducing apoptosis either through PERK-eIF2αATF4-CHOP-dependent or caspase-dependent pathways, whereas in malignancy, this ATF4-CHOP pathway is impaired by many factors; one being toll-like receptor (TLR) signaling [5]. Hence, it remains an enigma to discover the mechanism of, how cells decide whether to survive or die, ensuring the fine equilibrium between pro- and anti-apoptotic proteins and thus interpreting the complex nature of survival and apoptotic signals transmitted during the UPR. During chronic ER stress, when the sustained UPR signaling exceeds the time frame of adaptation limit, the chances of apoptosis gradually increase. Activation of protein kinases like JNK depend on IRE1, MAPK and apoptosis signal-regulating kinase 1 (ASK1) that further accelerates the apoptotic cascade under such circumstances [6]. Tumor necrosis factor receptor associated factor (TRAF2) signals the activated IRE1, leading to the ASK1 activation along with JNK phosphorylation and activation [7, 8]. Moreover, several BH-3 only proteins e.g., Bid and Bim are also the direct targets of JNK for apoptosis induction [9]. In the course of ER stress, ERAD mechanism removes abnormally folded proteins from ER with the help of ubiquitinmediated proteasomal degradation [10, 11]. Besides, the sternness of ER stress might modulate the comparable induction levels of specific UPR output pathways to manipulate cell-fate decisions in support of pro-death signals.

Reprogramming of Molecular Switching Events in UPR Driven ER Stress

mediated cellular adaptation and tolerance has rendered an attractive target for reprogramming to ensure prognostic efficacy towards cancer treatment. For this reprogramming, we have selected major members of ERS pathway and their prominent role as targets in ER stress-related diseases. UPR Mediated Cellular Adaptation and Tolerance Cellular response to the ER stress can be of various types; from the activation of survival pathways to initiate apoptosis that gradually scavenges out the damaged cells and maintain a fine balance of tolerance. Also, the types of stresses (whether protective or destructive) and the extent of the stress decide the fate of the strained cell [29]. Notably; there often exists an interchange between these signals that finally dictate the fate of the cells under stress. Distinct stress responses such as DNA damage, unfolded protein, and oxidative stress enhance the expression of stress regulatory proteins, thereby assisting series of events including protein folding, decreased protein influx load into the ER lumen, degradation of misfolded proteins, transient inhibition of mRNA translation, and apoptosis signal activation to clear the cells that are beyond the repair [30]. Irrespective of these individual signaling apparatus, all stress responses can subsequently converge into common cell death pathways, if the cell is unable to adapt to the stress condition. However, aberrant cellular stress signaling is directly linked with many human ailments including cancer. Hence, a better insight into these processes is required at the molecular level which can open manifold avenues for the target-based therapeutic intervention. Of note, new perspective into the mechanistic basis of stress responses will open multiple windows for the expansion of molecular targeted healing approaches and thus underscores a great potential for drug discovery. This purveyance nature of UPR mediated cellular adaptation and tolerance has rendered an attractive target for reprogramming of strained cells to ensure prognostic efficacy towards cancer treatment. For this reprogramming, we have selected major players of ERS pathway and their prominent role as targets in ER stress-related diseases.

REPROGRAMMING OF MOLECULAR SWITCHING EVENTS IN FAVOR OF APOPTOSIS UNDER ER STRESS CONDITIONS ER stress is shielded by the stimulation of the UPR, a homeostatic signaling network that coordinates the recuperation of ER function [31]. UPR controls the post-translational protein modification in ER by perceiving the protein load in the ER lumen, conveying the information into the nucleus, where it triggers a transcriptional program to reestablish ER homeostasis [32]. Incapability to cope up with the ER stress driven reprogramming, direct the cells to turn on apoptosis. This complex cellular response is orchestrated with the coordination of three transmembrane sensor proteins; viz: activating transcription factor 6 (ATF6), inositol-

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requiring enzyme 1 (IRE1) and protein kinase R-like endoplasmic reticulum kinase (PERK). In resting cells, the above said sensor proteins remain inactive by associating with ER chaperone, glucose regulated protein 78 kDa (GRP78). Accumulation of unfolded proteins dissociates GRP78 from these three sensor proteins, leading to their activation which, in turn, activates the UPR. The UPR initially initiates a prosurvival response to lessen the load of unfolded proteins and to reestablish ER homeostasis [33]. However, if the protein load is persistent and stress is not relieved, the pro-survival signaling switches into pro-apoptotic. The underlying mechanisms that direct this reprogramming of genes favoring apoptosis are now emerging. Therefore, to explore the mechanism by which, UPR mediated reprogramming turn on apoptosis with the help of three ER stress sensors viz: PERK, IRE1α, and ATF6, comprehensive studies are required. Targeting that escape of the cancer cells from therapy-induced apoptosis would help us to discover potential therapeutic strategies to reprogram the cellular events for apoptosis rather than survival and to overcome the issue of chemoresistance. Therapeutic Potential Against Cancer

of

Targeting

GRP78/Bip

The recent development of GRP78 research explains it as a novel biomarker for cancer progression and chemoresistance. The elevated GRP78 level, in human cancers, directly correlates with disease progression, recurrence and poor patient survival in almost all cancers including, breast, prostate, colon, gastric and hepatic carcinomas. Additionally, overexpression of GRP78 correlates with an increase in the dermal tumor mitotic index and increased tumor thickness [34]. These observations have focused the attention of researchers for anti-GRP78 drug discovery. Also, ample evidence revealed that knockdown of GRP78 suppressed cancer cell proliferation and increased chemosensitivity to therapies. SiRNA knockdown of GRP78 could severely impede the proliferation of glioma cells and increased sensitivity to chemotherapeutics such as temozolomide, CPT-11, and 5-fluorouracil [35]. Currently, there is a crave for a selective inhibitor of GRP78 as an anticancer agent in academia, industry and research sectors as well [3638]. GRP78 is an abundantly distributed chaperone protein that is confined to the ER lumen. However, according to the recent reports, a fraction of GRP78 also localizes to the surface of some malignant cells [39]. Recent literature also demonstrates that ER chaperones GRP78 and GRP94 are predictive biomarkers for cancer progression and malignancy [34, 40, 41]. The membranous expression of GRP78 in highly metastatic prostate cancer cells renders the essential role in signal transduction for proliferation and invasion. Finally, it is critical but not impossible to design rationally small molecule inhibitors of GRP78 that could specifically modulate its expression or the catalytic activity of GRP78 (important for its function) as a novel therapeutic strategy against such malignancy.

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Activation of Extracellular Par-4 Secretion and GRP78 Stabilization The tumor suppressor Par-4 (Prostate apoptosis response 4) is inexplicably downregulated in many cancers. A recent finding has shed new lights on the orientation and linking of tumor suppressor function with ER stress-induced extracellular pathway activation. In this recent finding, authors have clearly demonstrated the role of pro-apoptotic protein (Par-4) to maintain the cellular homeostasis during ER stress. Intriguingly, the intracellular Par-4 is cytoplasmic in its cellular localization, but during sustained ER-stressed condition, Par-4 is exported to Golgi and ER compartment to stabilize pro-survival protein GRP78 and thus mobilize GRP78 for cell death. TRAIL and Tunicamycin-treated prostate cancer cells have accelerated the secretion of the extracellular Par-4 to promote apoptosis in neighboring cells. In this context, inhibition of PERK kinase by siRNA has failed to induce apoptosis by Par-4 as well as co-localization of GRP78 and Par-4 in the ER compartment. As a molecular chaperone, GRP78 is well known for its tumor promoting activities as stressed cells need GRP78 for survival adaptation. In non-stressed cells, GRP78 interacts with ER sensor proteins; PERK, ATF6, and IRE1 eventually rendering them inactive. As soon as unfolded proteins dissociate GRP78 from its binding partners, the UPR pathway is activated. However, this does not completely deplete the whole GRP78 from ER lumen, rather a fraction of transmembrane GRP78 binds to pro-apoptotic protein Par-4 and activates extrinsic FAS-FADD pathway for triggering apoptosis. Though Par-4 could suppress pro-survival Bcl-2 proteins, it remains to be elucidated how the mitochondrial activation in ER stress favors the Par-4 function. Thus, the double-edged ER stress pathway seems to exhibit reminiscence of switching on-off machinery and largely function in cell type context. Targeting PERK Protein kinase R-like endoplasmic reticulum kinase (PERK), belonging to eIF2α kinase subfamily, is a fundamental transducer of ER stress that contributes in regulating vital cell functions. At some stage in UPR, the release of PERK from GRP78/BiP in the luminal domain of ER results in the oligomerization of free PERK inducing its autophosphorylation and the consequent phosphorylation of the translation initiation factor eIF2α, thus, tempering the general translation of proteins [42]. Nevertheless, selected mRNAs, including the one encoding the transcription factor ATF4 (activating transcription factor 4), acquire a selective advantage to continue translation during global translational shut-off [43]. ATF4, a 39 KDa protein, is a transcription factor that controls the regulation of several genes involved in restoring protein biosynthesis, protein folding, amino acid metabolism, autophagy and apoptosis [44]. Additionally, ATF4 augments the transcription of GADD153/CHOP and GADD34; the former is assumed to regulate the proapoptotic response [45], whereas the later helps to

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resume normal protein synthesis by directly interacting with the catalytic subunit of phosphatase PP1c and activating PP1’s ability to dephosphorylate eIF2α [46]. Furthermore, active PERK is involved in activation of NF-E2-related factor 2 (NRF2) by directly phosphorylating NRF2, which subsequently regulates the antioxidant response pathway by increasing the production of reduced glutathione [47-49]. Thus, PERK signaling has been strongly regarded as a major regulator of cancerous cells growth, as established by the fact that pharmacological inhibition of PERK impedes the growth of tumor in mouse xenograft models [50, 51]. Targeting IRE1 Inositol-requiring enzyme 1 (IRE1) is a transmembrane protein that exhibits dual enzyme activity (endoribonuclease activity domain and kinase activity domain) in its cytosolic C-terminal region reported to be involved in excision of non-specific mRNA as well as in the degradation of RNA (known as regulated IRE1-dependent decay, or RIDD) [52-54]. Upon ER stress, IRE1 regulates the induction of active transcription factor XBP1s by catalyzing the excision of a 26-nt intronic sequence from the XBP1 mRNA. The then activated XBP1s facilitates ER-associated degradation and regulates protein folding, their secretion and lipid synthesis [55]. Besides its role in the XBP1 mRNA splicing, IRE1α RNase directly degrades mRNAs via RIDD. As a result of RIDD, IRE1 cleaves multiple RNAs, including cancer-associated mRNAs such as PDFGR, SPARC, and Period1 mRNA [52] as well as cancer-associated microRNAs such as miR-17 or miR-96 [56] thus, contributing to tumor progression [57]. Moreover, recent reports also suggest that tumor angiogenesis is facilitated by the excised form of XBP1s, independent of vascular endothelial growth factor (VEGF), a well-known angiogenic factor [58]. Intriguingly, the Hypoxia-inducible factor-1α pathway induced in response to hypoxia constitutively activates XBPs, facilitating tumor development [59]. Together, these recent discoveries highlight the intricacy of the signaling pathways downstream of IRE1. Nonetheless; the previous literature provides additional insights into the UPR-dependent biologic networks that coordinate in regaining ER protein homeostasis. An in-depth knowledge of alterations in these signaling networks in cancer could unravel novel and unique therapeutic opportunities. Targeting ATF-6 Activating transcription factor (ATF-6), a transmembrane protein that possesses a transcriptional activity, when activated primarily controls the protein folding machinery of ER [60]. Once ER stress is induced, ATF-6 dissociated from GRP78 leaves the ER membrane to be transported to the Golgi, where the Golgi-resident site-1 and site-2 proteases carry out its sequential excision [61, 62]. The then generated 50 KDa functional fragment of ATF-6 translocates into the nucleus and regulates the

Reprogramming of Molecular Switching Events in UPR Driven ER Stress

expression of genes that serve chiefly in controlling protein folding machinery of ER and monitoring its quality [63, 64]. Although ATF-6 has been reported to resolve ER stress by regulating various genes associated with it and ATF-6 has also been documented to activate pro-apoptotic GADD153 [65]; this ambiguity in its (ATF-6) role still needs further research.

MOLECULAR MECHANISMS THAT MODULATES APOPTOSIS UNDER ER STRESS Restoring the cellular homeostasis is the prime objective of the ER stress response/UPR and is put to effect either by eradicating the stressful stimulus or by adapting to it. However, if the efforts to re-establish the homeostasis within the cell fall short and the acute imbalances persist, the pro-survival signals are withdrawn, and the proapoptotic events take over the command, ultimately leading to cell death. Therefore, the ER stress response can be considered as a cellular play between the two opposing principles- the cell death and survival. Different cellular mechanisms of ER stress-induced apoptosis are discussed in this segment, unveiling how CHOP/ GADD153, JNK, and BCL2 family proteins execute the pro-apoptotic signals eventually converging into cell death. The proapoptotic transcription factor CHOP (C/EBP homologous protein; GADD153) is the central player of PERK-mediated apoptosis during UPR. It is mainly upregulated by ATF4 and other UPR sensors like ATF6 and XBP1s via crosstalk with PERK/eIF2α and IRE1α/TRAF2/Ask1 pathways, consequently upregulating the transcription of CHOP [33, 66, 67]. However, CHOP upregulation has been demonstrated to be dependent on the PERK-eIF2α arm as both PERK−/−, ATF4−/− and eIF2α (Ser51Ala) knock-in cells did not show CHOP induction during ER stress [68-70]. Nevertheless, CHOP’s role as a proapoptotic transcription factor has been clearly shown both in vitro and in vivo. Furthermore, studies show that upon loss of CHOP, cancer cells become resistance to ER stress, signifying its role in introducing the cell death program [45, 71]. Additionally, the activity of CHOP is also controlled translationally and post-translationally, respectively, by the stability of CHOP mRNA [72] and p38MAPK phosphorylation, which augments its proapoptotic activity and may provide a link between IRE1 and PERK signaling pathways [72, 73]. Besides, CHOP loss-of-function protects the cell while CHOP gain-of-function imparts increased sensitivity towards various stimuli that disrupt the ER function, as disclosed by the genetic studies [45, 74]. One of the prime modes of CHOP-mediated apoptosis is through inhibition of pro-survival protein Bcl-2, which was evident from the correspondence between CHOP induction, oxidative stress, apoptosis and subsequent Bcl-2 downmodulation in a CHOPtransfected rat fibroblast cell line [74]. On the other hand, once Bcl-2 is restored via transfection, the CHOP-transfected cells are rescued from oxidative stress and the subsequent apoptosis. This effect

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exerted by CHOP may be attributed to its ability to interact with other transcriptional repressors that downregulate Bcl-2 transcription [74]. Additionally, to suppress anti-apoptotic Bcl-2, CHOP has been shown to activate classical intrinsic apoptosis, by regulating other Bcl-2 family members like Bim, Bad, Puma, Noxa etc., and translocation of Bax and Bak from ER to mitochondrial membrane [75-79]. Moreover, tribblesrelated protein 3 (TRB3), the other CHOP-regulator, plays an interesting role in molecular switching between pro-survival and pro-death functions of PERK pathway, by regulating CHOP in a negative feedback mechanism in mild ER stress. Conversely, the TRB3 expression is extremely robust during prolonged ER stress and is believed to inhibit Akt, thereby, directing the cell towards apoptosis [80]. Ohoka et al. showed that TRB3 knock down is necessary to facilitate apoptotic response in tunicamycin-treated HeLa cells [80]. Detailed studies are warranted to elucidate what role TRB3 exactly plays in ER stress-induced apoptosis. Upon induction of ER stress, IRE1 exerts its function to harmonize the ER folding ability with the urge of protein folding. Although IRE1 regulates protein folding during the demanding conditions of ER stress, its secondary function is to facilitate signaling events [81, 82]. Upon acute ER stress, activated IRE1 recruits the adapter molecule tumor-necrosis-factorreceptor-(TNFR)-associated factor 2 (TRAF2), thereby, leading to the activation of its downstream kinases, ASK1 and c-Jun N-terminal kinase (JNK) [8, 82]. Once activated, JNK inhibits ER resident anti-apoptotic Bcl-2 (B-cell lymphoma 2) family proteins by phosphorylation. Besides Bcl-2 inhibition via phosphorylation, JNK phosphorylates and activates proapoptotic BH3-only proteins, Bim (Bcl-2-interacting mediator of cell death), and Bid (BH3 interacting domain death agonist) thereby, facilitating proapoptotic effect. Together, these events lead to the execution of the intrinsic apoptotic process [83-86]. Thus, activation and/or posttranslational modification of BH3-only proteins possess a key role in setting the apoptotic cascade in action. Collectively, the above data advocates that JNK activation lead to the execution of apoptosis by Bax and Bak activation through ER stress-mediated suppression of BCL2. Moreover, IRE1 and TRAF2 pathways are also involved in the execution of mitochondrial-independent apoptosis by directly facilitating procaspase-4 activation [87]. Based on these reports, IRE1 is the final wing of the UPR to be activated and is central for the instigation of proapoptotic cascades, with PERK being the first, followed by ATF6. Upon activation, IRE1 activates XBP1 and induces UPR, but may eventually halt it by inducing P58IPK activation. So, if ER stress persists, IRE1 may recruit ASK1 and JNK to induce apoptosis, or otherwise, may return the cell to normal functioning. Thus, from such complex mechanism, it can be concluded that when the stress prolongs, PERK and IRE1 signaling cascades can converge, and mediate the induction of apoptosis. Thus, the above studies advocate PERK, ATF6, and IRE1 mediated

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UPR signaling, fundamental to ER stress-induced apoptosis. Although, a handful of recent evidence have shown that ATF6 induces CHOP mRNA expression during UPR signaling, its link to ER-stress induced cell death remains unveiled, thereby, giving a clue of its pro-survival role in ER stress condition. Conferring the leading role of PERK, ATF6, and IRE1 in UPR signaling, it is assumed that these UPR executors are also elemental to ER stress-induced apoptosis.

PERSPECTIVES Compounds/Molecules Reprogramming

that

Might

Induce

Molecules that might induce reprogramming or prolonged ER stress and consequently overcome cellular adaptation during ER stress opens a novel

avenue for the designing of lead molecules that might overcome the acquired resistance of tumor cells achieved during the UPR activation. Many molecules are capable of combating these cellular adaptations. It is because cancer cells often depend on upon various stress induced survival pathways, which can be trounced by inducing unrelenting cellular stress. Presently the drugs in this class include Paclitaxel, 5FU, or Bortezomib (Fig. 1). Table 1 shows various compound/molecules which have the innate potency to restructure the ER stress for cell death by activating pro-death signaling arms of UPR. Tea component epigallocatechin-3-gallate (EGCG) has been studied to exert antitumor activities by inhibiting GRP78 [88]. Microbial compound versipelostatin, blocks the activity of GRP78 transcriptional level but has no effect on GRP78 basal expression [89]. Versipelostatin, a macrocyclic compound primarily kills glucose-starved

Fig. (1). The schematic diagram represents the different arms of the UPR during ER stress. (A) Shows the PERK-dependent signaling pathways, (B) IRE1-dependent signaling pathways and (C) ATF6-dependent signals. The important targets which can be inhibited/ activated with various small molecules to reprogram UPR driven adaptive ER stress in favor of cell death are pointed out. Some of the agents which might reprogram ER stress at various target sites during ER stress as indicated in Fig. 1 and also mentioned below along with their target proteins.

Reprogramming of Molecular Switching Events in UPR Driven ER Stress

Table 1.

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Small molecules/compounds that regulate ER-stress mechanisms in diverse cancers.

Compound/Molecule

Mechanism/ Targets/ Pathways

Cancer Studied

Reference

Resveratrol (3,4',5 trihydroxystilbene)

Induction of GRP78 and CHOP-mediated apoptosis

Colon cancer

Park JW et al. [95]

Curcumin

PERK/CHOP-mediated apoptosis

Leukemia

Pae HO et al. [96]

Rottlerin

Upregulation of CHOP

Colon Cancer

Lim JH et al. [97]

Bortezomib and Ritonavir in combination

Induction of ER stress and increased levels of PERK, IRE1 & ATF6-mediated CHOP upregulation

Sarcoma

Kraus M et al. [98]

Panobinostat (pan-Histone Deacetylase

Inhibits the deacetylation of GRP78 and causes its dissociation from PERK, thereby, leads to PERK/CHOP- mediated apoptosis

Breast cancer

Rao R et al. [99]

Vorinostat

GRP78 acetylation, dissociation & activation of PERK

Prostate Cancer

Kahali S et al. [100]

Dihydroxyphenylethanol (DPE)

Activates two pathways:

Colon cancer

Guichard C et al. [101]

Nelfinavir

Induction of ER stress

Lung, Breast, Prostate Cancer

Gills JJ et al. [102]

Thioxotriazole Copper(II) Complex A0

Increases levels of XBPI mRNA, transient eIF2alpha phosphorylation, and a series of downstream cascades, including the halting of global protein synthesis and elevated expression of ATF4, CHOP, BIP, and GADD34.

Fibrosarcoma

Tardito S et al. [103]

Saquinavir

Induces ER stress

Ovarian cancer

McLean K et al. [104]

Shiga toxin 1(Shigella dysenteriae 1 and enterohaemorrhagic E. coli)

Increases levels of CHOP

Leukaemia

Lee SY et al. [104, 105]

Genistein

Increases levels of GADD153

Hepatocellular Carcinoma.

Yeh TC et al. [106]

Cannabinoids

Upregulate p8 stress protein, which in turn facilitates its apoptotic effect via induction of the ER stress-related genes ATF-4, CHOP, and TRB3.

Pancreatic cancer

Carracedo A et al. [107]

NPI-0052

Proteasome inhibitor

Multiple Myeloma, Advanced Cancers

Chauhan D et al. [108]

Carfilzomib (PR-171)

Selective proteasome inhibitor

Multiple Myeloma, Waldenstrom’s Macroglobulinemia

O’Connor OA et al. [109]

PS-341

Selective proteasome inhibitor

Multiple Myeloma.

Richardson PG et al. [110]

CEP-18770

Proteasome inhibitor

Multiple Myeloma, NonHodgkin’s lymphoma.

Piva R et al. [111]

Tanespimycin (17-AAG, (17Allylamino-17-

HSP90 Inhibitor

Gastrointestinal Tumors, Breast Cancer, Leukemia, Lymphoma,

Richardson PG et al. [112]

Prostate, Renal, and Thyroid Carcinoma.

Heath EI et al. [113]

Acute Myeloid leukemia, Advanced Carcinoma.

Kummar S et al. [115]

Inhibitor)

PERK-eIf2α IRE1-XBP1-GRP78

demethoxygeldanamycin), KOS-953) Alvespimycin (KOS-1022,

HSP90 Inhibitor

17-DMAG)

Pacey S et al. [114] Lancet JE et al. [116] Ramanathan RK et al. [117] Zismanov V et al. [118]

Retaspimycin (IPI-504)

HSP90 Inhibitor Phase

Gastrointestinal Stromal Tumors, Non-small Cell Lung and Prostate Cancer.

Hanson BE et al. [119]

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(Table 1) Contd…. Compound/Molecule

Mechanism/ Targets/ Pathways

PU-H71 Preclinical

HSP90 Inhibitor

studies

Cancer Studied

Reference

Breast Cancer,

Usmani SZ et al. [120]

Myeloma, Myeloproliferative

Caldas-Lopes E et al. [121]

Disorder.

Marubayashi S et al. [122] SNX-2112

HSP90 inhibitor

Gastric Cancer.

Bachleitner-Hofmann T et al. [123]

Oplopantriol A

Interferes with ubiquitin/proteasome pathway

Breast Cancer

Jin HR et al. [91]

Eeyarestatin I

Inhibitor of ER associated degradation (ERAD)

Hepatocellular Carcinoma.

Cross BCS et al. [124]

Versipelostatin

GRP78 inhibitor

Fibrosarcoma, Cervical Cancer.

Matsuo J et al. [125]

(-)-epigallocatechin gallate (EGCG)

GRP78 inhibitor

Breast Cancer

Luo T et al. [126]

Epidermal growth factor (EGF)-SubA

GRP78-targeting cytotoxin

Prostate Cancer

Backer JM et al. [37]

Irestatin

IRE1α inhibitor

Multiple Myeloma,

Feldman D et al. [127]

3-azido-withaferin A

Switches protective autophagy into apoptosis by suppressing BCL2 through Par-4 induction

Prostate Cancer

Rah B et al. [92]

cancer cells and interrupts components of the UPR, thus inhibiting tumor growth. Genistein, an active soy compound, has been reported to inhibit GRP78 expression [90]. Recently, Oplopantriol-A has shown evidence of anticancer potential which spontaneously stimulates ER stress-mediated cell killing by facilitating activation of BH3 proteins Noxa and Bim [91]. Further, we have recently demonstrated that 3-azido-withaferin A, a novel derivative of plant natural product withaferin A, induces ER stress-mediated protective autophagy at sub-toxic doses and reprograms these autophagic cells to apoptosis at a higher concentration (above its IC50 value) in a Par-4 dependent manner [92] (Table 2). Thus, the pharmacological concentration of these compounds might be a useful tool for targeting as well as reprogramming purpose in case of hypoxia or misfolded protein accumulation that conclude into ER stress and cancer progression. The caustic effect of increased blood supply and glucose deficiency in the tumor microenvironment accelerates the ER stress and further deposition of misfolded proteins inside these hypoxic cells could exaggerate the activation of stress sensors for adaptation to survive. There is a commencing of protection mechanism that renders overwhelming caring against even strongest chemotherapy regime. This particular feature in tumor development, UPR could be explored for reprogramming with small molecule inhibitors. Moreover, this protective mechanism has a limited capacity; as the stress prolongs, the pro-apoptotic module could trigger cell death, even in the presence of a surplus amount of GRP78 [93]. There is still void of knowledge about this molecular switching. It has been postulated that CHOP/GADD 153 has a pivotal role in this event. The base-line expression of CHOP is almost

diminished in normal cells and fairly insignificant in tumor cells. The expression of CHOP is firmly controlled by GRP78. As a result of intense ER stress, however, both normal and transformed cells fuel CHOP expression and the periodical abundance of CHOP level become a crucial factor in deciding the cell fate [94].

CONCLUDING REMARKS This review unveils, in detail, the remarkable progress in understanding the contribution of the UPR during ER stress in cancer, as a drug target for the pharmacotherapy. ER, as a vital cell organelle holds a key role in implementing and conducting various cellular functions. Under certain physiological or diseased conditions, the unfolded/misfolded proteins mount up in the ER lumen leading to the induction of ER stress which culminates into UPR. The UPR network is arranged as a nonlinear dynamic pathway in which multiple checkpoints determine the outputs of each UPR signaling branch. UPR components are part of distinct regulatory modules that orchestrate the finetuning of essential homeostatic processes that, in many cases, are beyond protein folding per se. There are many points that need to be addressed. Firstly, it is still puzzling how the UPR provides cell type-specific effects and how the information about the nature of the stimulus, its intensity, and its duration, is translated into particular cell fate programs that could be as contrasting as cell death, stress adaptation and cell differentiation, among other consequences. Secondly, the mechanism which decides the UPR dependent toggling between the pro-survival and pro-apoptotic signaling cascades remains unclear. A true focus on

Reprogramming of Molecular Switching Events in UPR Driven ER Stress

Table 2. S. No.

Class of Molecules

Chemical Name / Code / Common Name

1.

HSP90 inhibitors

Tanespimycin (17-Allylamino-17-demethoxy geldanamycin), Alvespimycin, PU-1771, SNX2112.

2.

ERAD inhibitors

Eeyarestatin1

3.

GRP78 inhibitors

Versipelostatin, Epigallocatechin gallate, Genistein

4.

IRE1α inhibitors

Irestatin

5.

ER stress inducers

Delta-9-tetrahydrocannabinoid, Bortezomib and Ritonavir in combination, Nelfinavir, Saquinavir

6.

GRP78 deacetylase inhibitors

Panobinostat (pan-histone- deacetylase inhibitor), Vorinostat

7.

CHOP upregulators

Resveratrol, Rottlerin, Genistein, Shiga toxin

8.

Par-4 inducers

3-azido withaferin A

Chemo-resistance towards drug-mediated cancer cell killing is a foremost challenge in front of clinicians and researchers. Therefore, a better understanding of the underlying mechanisms, and in particular how ER stress decides the cellular fate in response to chemotherapeutics would help us to discover new and more efficient pharmacophores, which could reprogram the cellular response to ER stress in favor of apoptosis rather than survival pathways. It would also pave the way for more effective strategies for the personalized treatment of cancer, based on a patient’s tumor cell type.

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CONFLICT OF INTEREST

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The authors declare no conflict of interest.

ACKNOWLEDGEMENTS We thank our director Dr. Ram A. Vishwakarma, for his valuable support in completion of this work. The authors also acknowledge Council of Scientific & Industrial Research and Department of Biotechnology, Govt. of India for providing fellowship.

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Agents that can reprogram ER stress at various target sites.

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