RIPK1-mediated induction of mitophagy compromises the viability of extracellular-matrix-detached cells

Article

Abstract

For cancer cells to survive during extracellular matrix (ECM) detachment, they must inhibit anoikis and rectify metabolic deficiencies that cause non-apoptotic cell death. Previous studies in ECM-detached cells have linked non-apoptotic cell death to reactive oxygen species (ROS) generation, although the mechanistic underpinnings of this link remain poorly defined. Here, we uncover a role for receptor-interacting protein kinase 1 (RIPK1) in the modulation of ROS and cell viability during ECM detachment. We find that RIPK1 activation during ECM detachment results in mitophagy induction through a mechanism dependent on the mitochondrial phosphatase PGAM5. As a consequence of mitophagy, ECM-detached cells experience diminished NADPH production in the mitochondria, and the subsequent elevation in ROS levels leads to non-apoptotic death. Furthermore, we find that antagonizing RIPK1/PGAM5 enhances tumour formation in vivo. Thus, RIPK1-mediated induction of mitophagy may be an efficacious target for therapeutics aimed at eliminating ECM-detached cancer cells.

Attributes

Attribute NameValues
Creator
  • Cassandra L. Gorsuch

  • Patrick Fagan

  • Chan Lee

  • Sun Eun Kim

  • Jens C. Hamann

  • Joshua A. Mason

  • Kelsey J. Weigel

  • Matyas Abel Tsegaye

  • Luqun Shen

  • Sydney Shuff

  • Junjun Zuo

  • Stephan Hu

  • Lei jJiang

  • Sarah Chapman

  • W. Matthew Leevy

  • Ralph J. DeBerardinis

  • Michael Overholtzer

  • Zachary T. Schafer

Journal or Work Title
  • Nature Cell Biology

Volume
  • 20

First Page
  • 272

Last Page
  • 284

Number of Pages
  • 12

Publication Date
  • 2018-03

Publisher
  • Nature

Date Created
  • 2018-10-31

Language
  • English

Departments and Units
Record Visibility and Access Public
Content License
  • All rights reserved

Digital Object Identifier

doi:10.1038/s41556-018-0034-2

This DOI is the best way to cite this article.