PERK integrates autophagy and oxidative stress responses to promote survival during extracellular matrix detachment
Autor: | Alvaro Avivar-Valderas, Chandandeep Nagi, Jayanta Debnath, Eduardo Salas, J. Alan Diehl, Julio A. Aguirre-Ghiso, Ekaterina Bobrovnikova-Marjon |
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Rok vydání: | 2011 |
Předmět: |
Cell Survival
ATG8 Green Fluorescent Proteins Immunoblotting Breast Neoplasms Biology Cell Line Extracellular matrix Mice eIF-2 Kinase Adenosine Triphosphate Mammary Glands Animal Autophagy Cell Adhesion Animals Humans Anoikis Molecular Biology Cells Cultured chemistry.chemical_classification Mice Knockout Reactive oxygen species EIF-2 kinase Kinase Endoplasmic reticulum Cell Biology Articles Fibroblasts Embryo Mammalian Cell biology Extracellular Matrix Enzyme Activation Oxidative Stress Carcinoma Intraductal Noninfiltrating chemistry Microscopy Fluorescence biology.protein RNA Interference Microtubule-Associated Proteins |
Zdroj: | Molecular and cellular biology. 31(17) |
ISSN: | 1098-5549 |
Popis: | 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. |
Databáze: | OpenAIRE |
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