PERK Integrates Oncogenic Signaling and Cell Survival During Cancer Development

Abstract

Unfolded protein responses (UPR), consisting of three major transducers PERK, IRE1, and ATF6, occur in the midst of a variety of intracellular and extracellular challenges that perturb protein folding in the endoplasmic reticulum (ER). ER stress occurs and is thought to be a contributing factor to a number of human diseases, including cancer, neurodegenerative disorders, and various metabolic syndromes. In the context of neoplastic growth, oncogenic stress resulting from dysregulation of oncogenes such as c-Myc, Braf(V600E) , and HRAS(G12V) trigger the UPR as an adaptive strategy for cancer cell survival. PERK is an ER resident type I protein kinase harboring both pro-apoptotic and pro-survival capabilities. PERK, as a coordinator through its downstream substrates, reprograms cancer gene expression to facilitate survival in response to oncogenes and microenvironmental challenges, such as hypoxia, angiogenesis, and metastasis. Herein, we discuss how PERK kinase engages in tumor initiation, transformation, adaption microenvironmental stress, chemoresistance and potential opportunities, and potential opportunities for PERK targeted therapy. J. Cell. Physiol. 231: 2088-2096, 2016. © 2016 Wiley Periodicals, Inc.

Figure 1. Activation of the UPR

Extracellular stress, intracellular stress as well as oncogene activation trigger ER stress and activate the transducers PERK, IRE-1 and ATF6. Extracullar stress includes viral infection, hypoxia, glucose deprivation, improper PH and pharmalogical interventions. Chemotherapeutic agents such as vemurafinib, paclitaxel and bortezomib induce ER stress in cancer cells. Intracellular stress such as redox imbalance, calcium imbalance, oxidized lipid and homocysteine result in unfolded protein response. Oncogenic stress such as cmyc amplification, BRAF mutation and HRas mutation all trigger ER stress. c-Myc greatly enhances the global transcription and translation, which cause large amount unfolded protein accumulated in the ER and activate PERK signaling. BRAF^V600E binds protein chaperon GRP78/Bip and dissociates Bip from the 3 transducers, activating IRE1 and PERK pathways. HRas^G12V causes activation of PERK and IRE1, also increases the Bip expression via direct or indirect way, the deep mechanisms are still unknown.

Figure 2. PERK signaling promotes cancer cell survival and aggressiveness

PERK phosphorylates its protein substrates Nrf2, eIF2α, FOXO and lipid substrate DAG. PERK phosphorylated Nrf2 dissociates from Keap1 and imported to nucleus, activating the transcription of drug resistance gene and redox enzyme genes. MRPs, multidrug resistance-associated proteins; MDRs, multidrug resistance proteins; GCLC, glutamate cysteine ligase catalytic subunit; GCLM, glutamate cysteine ligase modifier subunit; NQO1, NAD(P)H:quinone oxidoreductase 1; SODs, superoxide dismutases. PERK phosphorylated eIF2α exerts global protein inhibition, including cell cycle regulator cyclin D1 and lipid biosynthesis modulator insig1 (insulin inducible gene 1), which sequesters SREBP 1c (Sterol Regulatory Element Binding Protein) on the membrane to prevent its maturation. ACL, ATP citrate lyase; FAS, fatty acid synthase; SCD1, stearyl-CoA desaturase-1. eIF2α also selectively promotes some gene expression via alternative upstream open reading frame, such as ATF4 and VCIP. ATF4 activates CHOP transcription. ATF4, Chop alone or together regulate a broad range of genes, including those that regulate apoptosis, autophagy and hypoxia adaption. ATF4 regulated LAMP3 (Lysosomal-associated membrane protein 3) mediates migration and metastasis under ER stress. PERK activation of FOXO and phosphorylation DAG regulates the AKT function.

Figure 3. Pancreatic toxicity of PERK inhibition

PERK inhibition by either genetic deletion or pharmacological inhibition causes IFN signaling increase in pancreas and accumulation of misfolded insulin, proinsulin and glucose transporters Glut2, leading to hyperglycermia and diabetes. In human, PERK inactivation mutation results in Wlocott-Rallison syndrome, which is characterized with pancreatic degeneration and diabetes.