Targeting the Integrated Stress Response in Cancer Therapy

Abstract

The integrated stress response (ISR) is an evolutionarily conserved intra-cellular signaling network which is activated in response to intrinsic and extrinsic stresses. Various stresses are sensed by four specialized kinases, PKR-like ER kinase (PERK), general control non-derepressible 2 (GCN2), double-stranded RNA-dependent protein kinase (PKR) and heme-regulated eIF2α kinase (HRI) that converge on phosphorylation of serine 51 of eIF2α. eIF2α phosphorylation causes a global reduction of protein synthesis and triggers the translation of specific mRNAs, including activating transcription factor 4 (ATF4). Although the ISR promotes cell survival and homeostasis, when stress is severe or prolonged the ISR signaling will shift to regulate cellular apoptosis. We review the ISR signaling pathway, regulation and importance in cancer therapy.

Keywords: ATF4; CHOP; apoptosis; cancer treatment; integrated stress responses.

FIGURE 1

Integrated stress responses signaling pathway. ER stress, mitochondria stress or heme depletion, amino acid deficiency and ds-RNA virus infection activate PERK, HRI, GCN2 and PKR sensor kinases, leading to phosphorylation of eIF2α. eIF2α phosphorylation causes global inhibition of protein synthesis but selective translation of ATF4 mRNA. ATF4 binds to DNA targets to regulate the expression of genes that promote cellular adaptation, survival and apoptosis. Feedback regulation of ISR is regulated by constitutively expressed phosphatase complex CReP-PP1 and inducible phosphatase GADD34-PP1, which dephosphorylate eIF2α and attenuate or terminate ISR. AA, Amino acid; ER, Endoplasmic reticulum.

FIGURE 2

Cell death, pro-survival, tumor progression and chemoresistance pathways of ISR. ATF4 directly or indirectly controls the transcription of apoptotic, adaptive, tumor progression and chemoresistance genes. When stress persists (for example, drug treatments) and cancer cells are unable to adapt to and reach homeostasis though the activation of ISR, ATF4 shifts this balance towards apoptosis by inducing apoptotic genes. AA, Amino acid.

FIGURE 3

Manipulation of ISR in cancer therapy. ATF4 induction can be achieved either through kinase activators such as bortezomib, gemcitabline, lopinavir, CCT020312, halofuginone, arginine deiminase, STAT3 inhibitors, BEPP, BTdCPU and ONC201 or the inhibitors of phosphatases such as salubrinal, guanabenz and nelfinavir. In the case of ISR promotes cancer cell survival and resistant to therapeutic treatments, inhibition of ATF4 can be achieved by kinase inhibitors such as LY-4, GSK2606414, AMG-44, BCR-ABL inhibitors, SP600125, C16 and aminopyranzolindane or compound ISRIB downstream of eIF2α phosphorylation.