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Monitoring Stub1-Mediated Pexophagy
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Monitoring Stub1-Mediated Pexophagy

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

Alvaro Avivar-Valderas1, Eduardo Salas, Ekaterina Bobrovnikova-Marjon

  • 1Department of Medicine, Tisch Cancer Institute, Black Family Stem Cell Institute, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA.

Molecular and Cellular Biology
|June 29, 2011
PubMed

Insights

The endoplasmic reticulum kinase PERK promotes survival of detached mammary epithelial cells by enhancing autophagy and antioxidant responses, delaying anoikis. This pathway is dysregulated in breast cancer, suggesting a role in tumor cell survival.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Mammary epithelial cells (MECs) undergo anoikis (programmed cell death) upon detachment from the extracellular matrix (ECM).
  • Detachment triggers reactive oxygen species (ROS) production and autophagy, with their balance influencing cell fate.
  • The role of the endoplasmic reticulum stress response in mediating survival during ECM detachment is not fully understood.

Purpose of the Study:

  • To investigate the role of the endoplasmic reticulum kinase PERK in MEC survival following ECM detachment.
  • To elucidate the molecular mechanisms by which PERK influences autophagy, ATP production, and antioxidant responses.
  • To examine the relevance of the PERK pathway in normal and cancerous human breast tissues.

Main Methods:

  • Loss-of-function studies using mammary epithelial cells.
  • Analysis of the PERK-eukaryotic translation initiation factor 2α (eIF2α)-ATF4-CHOP pathway.
  • Assessment of autophagy regulators (ATG6, ATG8), ATP levels, and ROS production.
  • In vivo studies using inducible PERK chimera activation.
  • Analysis of PERK and LC3 protein levels in mouse and human breast tissues.

Main Results:

  • ECM detachment activates the PERK pathway, leading to increased autophagy, sustained ATP levels, and reduced ROS.
  • This PERK-mediated response delays anoikis in detached MECs.
  • Activation of a PERK chimera promotes lumen formation in mammary epithelial acini.
  • PERK and LC3 levels are decreased in PERK-deficient mammary glands but elevated in human breast ductal carcinoma in situ (DCIS) compared to normal tissues.

Conclusions:

  • The PERK pathway is a critical mediator of survival for ECM-detached mammary epithelial cells.
  • PERK coordinates autophagy, ATP production, and antioxidant defenses to prevent anoikis.
  • Dysregulation of the PERK pathway, with increased PERK and LC3, is observed in human DCIS, suggesting its potential role in promoting tumor cell survival.

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