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

Therapeutic Approaches

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

Lamy, Laurence; Ngo, Vu N; Emre, N C Tolga; Shaffer, Arthur L; Yang, Yandan; Tian, Erming; Nair, Vinod; Kruhlak, Michael J; Zingone, Adriana; Landgren, Ola; Staudt, Louis M;

Keywords

  • Apoptosis/ drug effects
  • Apoptosis/ physiology
  • Autophagy/ drug effects
  • Autophagy/ physiology
  • Caspase 10/ genetics
  • Caspase 10/ metabolism
  • Caspase Inhibitors/ pharmacology
  • Cell Line, Tumor
  • Cell Survival/ drug effects
  • Cell Survival/ physiology
  • Gene Knockdown Techniques
  • Humans
  • Multiple Myeloma/ drug therapy
  • Multiple Myeloma/ enzymology
  • Multiple Myeloma/ genetics
  • Multiple Myeloma/ pathology
  • RNA Interference

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