PERK integrates autophagy and oxidative stress responses to promote survival during extracellular matrix detachment

Alvaro Avivar-Valderas, Eduardo Salas, Ekaterina Bobrovnikova-Marjon, J. Alan Diehl, Chandandeep Nagi, Jayanta Debnath, Julio A. Aguirre-Ghiso

Research output: Contribution to journalArticlepeer-review

196 Scopus citations

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 2α (eIF2α)-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-ΔNPERK 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.

Original languageEnglish (US)
Pages (from-to)3616-3629
Number of pages14
JournalMolecular and cellular biology
Volume31
Issue number17
DOIs
StatePublished - Sep 2011
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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