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Cancer Cell. 2013 Apr 15;23(4):435-49. doi: 10.1016/j.ccr.2013.02.017. Epub 2013 Mar 28.

Control of autophagic cell death by caspase-10 in multiple myeloma.

Author information

1
Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA.

Abstract

We performed a loss-of-function RNA interference screen to define therapeutic targets in multiple myeloma, a genetically diverse plasma cell malignancy. Unexpectedly, we discovered that all myeloma lines require caspase-10 for survival irrespective of their genetic abnormalities. The transcription factor IRF4 induces both caspase-10 and its associated protein cFLIPL in myeloma, generating a protease that does not induce apoptosis but rather blocks an autophagy-dependent cell death pathway. Caspase-10 inhibits autophagy by cleaving the BCL2-interacting protein BCLAF1, itself a strong inducer of autophagy that acts by displacing beclin-1 from BCL2. While myeloma cells require a basal level of autophagy for survival, caspase-10 tempers this response to avoid cell death. Drugs that disrupt this vital balance may have therapeutic potential in myeloma.

PMID:
23541952
PMCID:
PMC4059832
DOI:
10.1016/j.ccr.2013.02.017
[Indexed for MEDLINE]
Free PMC Article

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