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Nat Chem Biol. 2016 Jul;12(7):497-503. doi: 10.1038/nchembio.2079. Epub 2016 May 9.

Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis.

Author information

1
Department of Biological Sciences, Columbia University, New York, New York, USA.
2
Department of Pharmacology, Columbia University, New York, New York, USA.
3
Quantitative Proteomics Center, Columbia University, New York, New York, USA.
4
Department of Chemistry, Columbia University, New York, New York, USA.

Abstract

Apoptosis is one type of programmed cell death. Increasingly, non-apoptotic cell death is recognized as being genetically controlled, or 'regulated'. However, the full extent and diversity of alternative cell death mechanisms remain uncharted. Here we surveyed the landscape of pharmacologically accessible cell death mechanisms. In an examination of 56 caspase-independent lethal compounds, modulatory profiling showed that 10 compounds induced three different types of regulated non-apoptotic cell death. Optimization of one of those ten resulted in the discovery of FIN56, a specific inducer of ferroptosis. Ferroptosis has been found to occur when the lipid-repair enzyme GPX4 is inhibited. FIN56 promoted degradation of GPX4. FIN56 also bound to and activated squalene synthase, an enzyme involved in isoprenoid biosynthesis, independent of GPX4 degradation. These discoveries show that dysregulation of lipid metabolism is associated with ferroptosis. This systematic approach is a means to discover and characterize novel cell death phenotypes.

PMID:
27159577
PMCID:
PMC4920070
DOI:
10.1038/nchembio.2079
[Indexed for MEDLINE]
Free PMC Article

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