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

Mark A. Hawk, Cassandra L. Gorsuch, Patrick Fagan, Chan Lee, Sung Eun Kim, Jens C. Hamann, Joshua A. Mason, Kelsey J. Weigel, Matyas Abel Tsegaye, Luqun Shen, Sydney Shuff, Junjun Zuo, Stephan Hu, Lei Jiang, Sarah Chapman, W. Matthew Leevy, Ralph J. Deberardinis, Michael Overholtzer, Zachary T. Schafer

Research output: Contribution to journalArticlepeer-review

63 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)272-284
Number of pages13
JournalNature Cell Biology
Volume20
Issue number3
DOIs
Publication statusPublished - 2018 Mar 1
Externally publishedYes

Bibliographical note

Funding Information:
We thank Veronica Schafer, all current and past Schafer lab members, James Clancy, Crislyn D’Souza-Schorey, H. Clay Conner, Athanasia Panopoulos, Ian Guldner, Siyuan Zhang, Rebecca Wingert and Paul Huber for helpful comments, experimental assistance and valuable discussion. We thank Jeffrey Hawk, Janet Hawk and Veronica Wende for helpful comments and support. We also thank Leta Nutt (St. Jude Children’s Research Hospital) for the Bax(−/−)/Bak(−/−) MEFs, Mary Ann McDowell (Notre Dame) for assistance with immunofluorescence, Kevin T. Vaughan (Notre Dame) for help with soft agar and William Archer (Notre Dame) for guidance with immunofluorescence. This work was supported by a Lee National Denim Day Research Scholar Grant (RSG-14-145-01-CSM) from the American Cancer Society (to Z.T.S.), a research grant from the Phi Beta Psi National Project (to Z.T.S.), a National Science Foundation Graduate Research Fellowship grant DGE 1313583 (to M.A.H.), the Coleman Foundation (Chicago, IL), and funds from Ron and Rosemarie Malanga.

Publisher Copyright:
© 2018 The Author(s).

ASJC Scopus subject areas

  • Cell Biology

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