PERK Integrates Autophagy and Oxidative Stress Responses To Promote Survival during Extracellular Matrix Detachment

Abstract

Mammary epithelial cells (MECs) detached from the extracellular matrix (ECM) produce deleterious reactive oxygen species (ROS) and induce autophagy to survive. The coordination of such opposing responses likely dictates whether epithelial cells survive ECM detachment or undergo anoikis. Here, we demonstrate that the endoplasmic reticulum kinase PERK facilitates survival of ECM-detached cells by concomitantly promoting autophagy, ATP production, and an antioxidant response. Loss-of-function studies show that ECM detachment activates a canonical PERK-eukaryotic translation initiation factor 2␣ (eIF2␣)-ATF4-CHOP pathway that coordinately induces the autophagy regulators ATG6 and ATG8, sustains ATP levels, and reduces ROS levels to delay anoikis. Inducible activation of an Fv2E-⌬NPERK chimera by persistent activation of autophagy and reduction of ROS results in lumen-filled mammary epithelial acini. Finally, luminal P-PERK and LC3 levels are reduced in PERK-deficient mammary glands, whereas they are increased in human breast ductal carcinoma in situ (DCIS) versus normal breast tissues. We propose that the normal proautophagic and antioxidant PERK functions may be hijacked to promote the survival of ECM-detached tumor cells in DCIS lesions.

MIST1 Links Secretion and Stress as both Target and Regulator of the Unfolded Protein Response

“…As shown in Fig. 1H, CHOP expression was induced by all treatments, consistent with activation of the PERK pathway in response to both ER stress and oxidative stress (42). In contrast, Xbp1s transcript and protein levels were induced only in cells treated with the two ER stress agents (Fig.…”

Anoikis evasion in inflammatory breast cancer cells is mediated by Bim-EL sequestration

“…Given that the interaction of Beclin-1 with LC8 and Bim-EL has been shown to prevent Beclin-1 from initiating autophagosome formation, 38 it seems reasonable to speculate that ECMdetached IBC cells are defective in autophagy in addition to anoikis. This presents a unique problem for these cells, as autophagy has previously been shown to be critical for the survival of ECM-detached cells, 46,47 presumably to facilitate nutrient consumption. Perhaps this defect could be overcome through changes in glucose or fatty acid metabolism that have previously been reported in ECM-detached cells.…”

Anoikis: an emerging hallmark in health and diseases

“…Indeed, the RNA activated protein kinaselike endoplasmic reticulum kinase (PERK) facilitates the survival of ECM-detached cells by concomitantly promoting autophagy and ATP production [72]. ECM detachment activates the canonical autophagic pathway through ATG6 and ATG8, sustains ATP levels and delays anoikis.…”

“…ECM detachment activates the canonical autophagic pathway through ATG6 and ATG8, sustains ATP levels and delays anoikis. The functional players of such integration are Beclin-1, an autophagic protein acknowledged to modulate the anti-apototic role of Bcl-2 and Bcl-XL [73], ROS and ERKs [72]. Autophagy allows epithelial cells to survive given that they re-adhere onto the ECM in a timely fashion, and it is likely a previously unrecognized tool used by circulating cancer cells to survive anoikis, thereby facilitating tumour cell dormancy though nutrient recovery, as well as dissemination of metastases [74].…”