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

Mark A HawkCassandra L GorsuchPatrick FaganChan LeeSung Eun KimJens C HamannJoshua A MasonKelsey J WeigelMatyas Abel TsegayeLuqun ShenSydney ShuffJunjun ZuoStephan HuLei JiangSarah ChapmanW Matthew LeevyRalph J DeBerardinisMichael OverholtzerZachary T Schafer
Published in: Nature cell biology (2018)
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.
Keyphrases
  • cell death
  • extracellular matrix
  • cell cycle arrest
  • reactive oxygen species
  • induced apoptosis
  • protein kinase
  • oxidative stress
  • cell proliferation
  • small molecule