title: Control of autophagic cell death by caspase-10 in multiple myeloma.
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.
authors.affiliation: Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA.
authors.forename: Laurence
authors.initials: L
authors.lastname: Lamy
authors.forename: Vu N
authors.initials: VN
authors.lastname: Ngo
authors.forename: N C Tolga
authors.initials: NC
authors.lastname: Emre
authors.forename: Arthur L
authors.initials: AL
authors.lastname: Shaffer
authors.forename: Yandan
authors.initials: Y
authors.lastname: Yang
authors.forename: Erming
authors.initials: E
authors.lastname: Tian
authors.forename: Vinod
authors.initials: V
authors.lastname: Nair
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kruhlak
authors.forename: Adriana
authors.initials: A
authors.lastname: Zingone
authors.forename: Ola
authors.initials: O
authors.lastname: Landgren
authors.forename: Louis M
authors.initials: LM
authors.lastname: Staudt
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D053455:Caspase 10 / Q000235:genetics* / Q000378:metabolism*; D061945:Caspase Inhibitors / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D055785:Gene Knockdown Techniques; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D034622:RNA Interference
chemical_list: D061945:Caspase Inhibitors; D053455:Caspase 10
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