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Review
. 2016;16(6):533-44.
doi: 10.2174/1566524016666160523143937.

The Role of the PERK/eIF2α/ATF4/CHOP Signaling Pathway in Tumor Progression During Endoplasmic Reticulum Stress

W Rozpedek, D Pytel  1 , B Mucha, H Leszczynska, J A Diehl, I Majsterek  2
Affiliations
Review

The Role of the PERK/eIF2α/ATF4/CHOP Signaling Pathway in Tumor Progression During Endoplasmic Reticulum Stress

W Rozpedek et al. Curr Mol Med. 2016.

Abstract

Hypoxia is a major hallmark of the tumor microenvironment that is strictly associated with rapid cancer progression and induction of metastasis. Hypoxia inhibits disulfide bond formation and impairs protein folding in the Endoplasmic Reticulum (ER). The stress in the ER induces the activation of Unfolded Protein Response (UPR) pathways via the induction of protein kinase RNA-like endoplasmic reticulum kinase (PERK). As a result, the level of phosphorylated Eukaryotic Initiation Factor 2 alpha (eIF2α) is markedly elevated, resulting in the promotion of a pro-adaptive signaling pathway by the inhibition of global protein synthesis and selective translation of Activating Transcription Factor 4 (ATF4). On the contrary, during conditions of prolonged ER stress, pro-adaptive responses fail and apoptotic cell death ensues. Interestingly, similar to the activity of the mitochondria, the ER may also directly activate the apoptotic pathway through ER stress-mediated leakage of calcium into the cytoplasm that leads to the activation of death effectors. Apoptotic cell death also ensues by ATF4-CHOP- mediated induction of several pro-apoptotic genes and suppression of the synthesis of anti-apoptotic Bcl-2 proteins. Advancing molecular insight into the transition of tumor cells from adaptation to apoptosis under hypoxia-induced ER stress may provide answers on how to overcome the limitations of current anti-tumor therapies. Targeting components of the UPR pathways may provide more effective elimination of tumor cells and as a result, contribute to the development of more promising anti-tumor therapeutic agents.

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Figures

Fig. (1)
Fig. (1)
PERK-dependent Unfolded Protein Response. Under normal physiological conditions, ER transmembrane receptor PERK is present in an inactive state, since it is associated with BiP chaperones. As a response to the accumulation of unfolded or misfolded proteins within ER lumen, under ER stress, BiP dissociates from the lumenal domain of PERK. This leads to oligomerization and trans-autophosphorylation of PERK, which becomes an active kinase with the ability to phosphorylate α subunits of the eIF2. The result is suppression of global protein translation, which causes the cell cycle to arrest in the G1 phase as well as the induction of preferential translation of ATF4, which upregulates expression of genes responsible for restoring cell homeostasis. Under prolonged ER stress, when pro-adaptive UPR fails, PERK may also trigger pro-apoptotic signals through activation of downstream CHOP, which promotes apoptosis.
Fig. (2)
Fig. (2)
Mechanisms of initiation of translation. eIF2α-GTP complex binds to (Met)-tRNAi that forms a ternary complex, which associates with 40S ribosomal subunit and combines with eIF1, eIF1A and eIF3 resulting in the creation of pre-initiation complex 43S. This combines with both mRNA and heterotetramer eIF4F. Afterwards, the anticodon of (Met)-tRNAi pairs with the AUG codon of mRNA, which forms the 48S pre-initiation complex. That process requires consumption of energy, since GTP is hydrolysed to GDP. Subsequently, complex eIF2α-GDP and other initiator factors are released. After association of the 60S subunit of the ribosome with the 48S pre-initiation complex, the complete 80S initiation complex is created. Formation of a new ternary complex requires replacement of GDP to GTP by eIF2β. The process is inhibited by phosphorylation of eIF2α by PERK under stress conditions of the ER, which results in attenuation of global protein translation and triggers preferential translation of selected genes such as ATF4.
Fig. (3)
Fig. (3)
ER stress-mediated apoptosis. ER and mitochondria may directly initiate signaling pathways for the activation of the caspase cascade that results in apoptotic cell death. Members of all classes of the Bcl-2 family of proteins localize not only to the outer mitochondrial membrane, but also to the ER membrane. The anti-apoptotic Bcl-2 members of family proteins may inhibit activation of pro-apoptotic Bcl-2 proteins such as Bax/Bak. Under ER stress conditions active BH3 domain-only proteins trigger the oligomerization of pro-apoptotic proteins like Bax and Bak, creation of Bax/Bak pores within mitochondrial outer membrane, and subsequently its permeabilization. As a consequence, cytochrome c is released into the cell cytosol where it binds to Apaf-1 and procaspase-9 and forms an apoptosome complex. This triggers the activation of the caspase cascade, which finally may elicit mitochondria-mediated apoptosis. On the other hand, prolonged ER stress can trigger caspase-12-mediated apoptosis. Caspase-12, associated with the cytoplasmic face of the ER membrane, is activated under chronic ER stress in response to calcium leakage from the ER lumen. This leads to rapid activation of the calcium-calpain-caspase-12-caspase-3 cascade and, as a result, ER stress induced apoptotic cell death ensues.
Fig. (4)
Fig. (4)
Mechanisms of CHOP-induced apoptosis under prolonged ER stress. Sustained PERK-mediated phosphorylation of eIF2α and increased expression of ATH4 under prolonged stress conditions of the ER lead to CHOP-induced apoptotic cell death through various signaling pathways. CHOP transcriptionally attenuates Bcl-2 anti-apoptotic family of proteins and adversely activates the pro-apoptotic BH3- domain only proteins, such as BIM. Moreover, CHOP directly activates the expression of GADD34 genes, in which the products create a complex with PP1 resulting in dephosphorylation of eIF2α and inhibition of PERK-mediated translational attenuation. CHOP also markedly enhances expression of ERO1α genes. ERO1α, oxidoreductase ER enzyme, generates ER-localized H2O2, thus causing a hyperoxidized environment in the ER lumen. ERO1α also binds to the ER calcium channels IP3R1 and promotes release of calcium ions into the cell cytosol. As a consequence, calcium-sensing enzyme CaMKII is activated, which, in turn, triggers induction of NADPH oxidase subunit 2 (NOX2) and subsequent generation ROS, that through a positive feedback loop causes activation of CaMKII, thereby promoting expression of genes DDIT3 that encode transcription factor CHOP.
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