Mechanism Of Anti-Myeloma Effects Due To Silencing Of Deptor

TL;DRAbstract

DEPTOR is a recently described 48 kDa protein that binds to mTOR and inhibits this kinase within TORC1 and TORC2 complexes. Over-expression of DEPTOR specifically occurs in the multiple myeloma genetic sub-class that contains IgH translocations. Most interestingly, DEPTOR knock-down in over-expressing MM cell lines induces growth arrest and apoptosis, indicating DEPTOR could serve as a therapeutic target in selected patients. To investigate the mechanism of MM cytoreduction induced by DEPTOR silencing we generated a doxycycline-inducible DEPTOR shRNA. Induced DEPTOR knockdown in 8226 and OPM-2 cell lines resulted in phosphorylation of p70S6K and 4E-BP1 (due to release of TORC1 inhibition) as well as apoptosis, cell cycle arrest and senescence. RAPTOR knockdown in these MM cells prevented TORC1 stimulation and the anti-MM effects resulting from DEPTOR silencing. Thus, the acute activation of TORC1 mediated the apoptosis and growth arrest. Although DEPTOR silencing and mTORC1 activation

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