期刊
NATURE CELL BIOLOGY
卷 20, 期 3, 页码 272-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41556-018-0034-2
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资金
- Lee National Denim Day Research Scholar Grant from the American Cancer Society [RSG-14-145-01-CSM]
- Phi Beta Psi National Project
- National Science Foundation Graduate Research Fellowship [DGE 1313583]
- Coleman Foundation (Chicago, IL)
- Ron and Rosemarie Malanga
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.
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