Multiple Myeloma Cells Require Caspase-10

The high degree of genetic heterogeneity of multiple myeloma, a largely incurable malignancy of the plasma cells of the bone marrow, constitutes a major obstacle to its successful treatment. Lamy and colleagues performed an RNA interference screen to identify genes specifically essential for the survival of multiple myeloma cells but not other hematologic cancers. Strikingly, small hairpin RNAs targeting caspase-10 were selectively toxic to all multiple myeloma cell lines tested, regardless of their underlying genetic abnormalities. Caspase-10 initiates apoptosis upon ligand engagement of tumor necrosis factor receptors, but apoptotic markers were not induced upon caspase-10 knockdown in multiple myeloma cells, indicating that caspase-10 suppresses a nonapoptotic form of cell death in the context of this disease. Consistent with these findings, multiple myeloma cells in which caspase-10 was genetically or pharmacologically inhibited showed characteristic morphologic features of autophagy, and knockdown of beclin-1, a known inducer of autophagy, rescued the effects of caspase-10 inhibition on multiple myeloma cell viability. Caspase-10 protease activity was required for multiple myeloma cell viability and led to the cleavage of BCL2-associated transcription factor 1 (BCLAF1), a protein originally identified based on its ability to bind antiapoptotic BCL2 family members. BCLAF1 was necessary for cell death following caspase-10 inhibition and was found to induce autophagy when overexpressed. Upon caspase-10 inhibition, the interaction between BCLAF1 and BCL2 significantly increased, whereas the interaction between beclin-1 and BCL2, which normally sequesters beclin-1 to prevent the induction of autophagy, decreased, suggesting a mechanism whereby caspase-10 inhibits autophagic cell death in multiple myeloma cells by cleaving BCLAF1 and preventing dissociation of beclin-1 from BCL2. Given that genetically diverse cell lines were similarly addicted to caspase-10, drugs targeting this autophagic regulatory pathway may overcome challenges posed by multiple myeloma heterogeneity.

Lamy L, Ngo VN, Emre NC, Shaffer AL 3rd, Yang Y, Tian E, et al. Control of autophagic cell death by caspase-10 in multiple myeloma. Cancer Cell 2013;23:435–49.

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