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Blood, 15 April 2005, Vol. 105, No. 8, pp. 3255-3262.
Prepublished online as a Blood First Edition Paper on December 21, 2004; DOI 10.1182/blood-2004-10-3984.
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NEOPLASIA
Evidence for a protective role of Mcl-1 in proteasome inhibitor-induced apoptosis
Alessio Nencioni,
Fei Hua,
Christopher P. Dillon,
Rayka Yokoo,
Christoph Scheiermann,
Mike H. Cardone,
Eleonora Barbieri,
Ilaria Rocco,
Anna Garuti,
Sebastian Wesselborg,
Claus Belka,
Peter Brossart,
Franco Patrone, and
Alberto Ballestrero
From the Massachusetts Institute of Technology, Department of Biology, Center for Cancer Research, Cambridge, MA; the Department of Internal Medicine, University of Genova, Italy; Merrimack Pharmaceuticals, Cambridge, MA; the Department of Internal Medicine I, the Department of Radiation Oncology, and the Department of Hematology, Oncology and Immunology, University of Tübingen, Germany.
Proteasome inhibitors exhibit antitumor activity against malignancies of different histology. Yet, the mechanisms underlying this effect are poorly understood. Recent evidence indicates that antiapoptotic factors may also accumulate as a consequence of exposure to these drugs, possibly reducing their cytotoxicity. These include the Bcl-2 family member Mcl-1, whose down-regulation has been proposed to initiate apoptosis in response to genotoxic stimuli. In this study, we found that proteasome inhibitors release cyotochrome c and second mitochondria-derived activator of caspase (SMAC)/Diablo and trigger the subsequent apoptotic cascade in spite of concomitant Mcl-1 increase. However, our data indicate that subtraction of Mcl-1 during apoptosis, although not required for early release of proapoptotic factors, is probably relevant in speeding up cell demise, since RNA interference-mediated Mcl-1 silencing is lethal in lymphoma cells. Consistent with this, the cytotoxic effects of proteasome inhibitors are enhanced when Mcl-1 increase is impeded. Thus, this study identifies Mcl-1 accumulation as an unwanted molecular consequence of exposure to proteasome inhibitors, which slows down their proapoptotic effects. Pharmacologic or genetic approaches targeting Mcl-1, including therapeutic RNAi, may increase the effectiveness of these compounds. (Blood. 2005;105:3255-3262)
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