Control of Autophagic Cell Death by Caspase-10 in Multiple Myeloma
Menée sur des lignées cellulaires, cette éude met en évidence un mécanisme par lequel, en régulant la mort cellulaire autophagique, la caspase 10 favorise la survie des cellules cancéreuses, quelles que soient leurs anomales génétiques
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.
º Caspase-10 activity maintains myeloma cell survival
º cFLIP drives caspase-10 activation in multiple myeloma
º Caspase-10 blocks autophagic cell death in myeloma
º Caspase-10 promotes survival by cleaving BCLAF1, an inducer of autophagic death
Cancer cell , article en libre accès, 2012