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Up-Regulation of c-Jun Inhibits Proliferation and Induces Apoptosis via Caspase-Triggered c-Abl Cleavage in Human Multiple Myeloma

¹ Jerome Lipper Multiple Myeloma Center, Medical Oncology, and ² Department of Medical Oncology and Center for Applied Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; and ³ Laboratory of Cell Signaling, Dulbecco Telethon Institute and University of Tor Vergata, Rome, Italy

Requests for reprints: Kenneth C. Anderson or Klaus Podar, Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115. Phone: 617-632-2144; Fax: 617-632-2140; E-mail: kenneth_anderson{at}dfci.harvard.edu or klaus_podar{at}dfci.harvard.edu.

Here we show the antimyeloma cytotoxicity of adaphostin and carried out expression profiling of adaphostin-treated multiple myeloma (MM) cells to identify its molecular targets. Surprisingly, c-Jun was the most up-regulated gene even at the earliest point of analysis (2 h). We also observed adaphostin-induced c-Abl cleavage in immunoblot analysis. Proteasome inhibitor bortezomib, but not melphalan or dexamethasone, induced similar effects, indicating unique agent-dependent mechanisms. Using caspase inhibitors, as well as caspase-resistant mutants of c-Abl (TM-c-Abl and D565A-Abl), we then showed that c-Abl cleavage in MM cells requires caspase activity. Importantly, both overexpression of the c-Abl fragment or c-Jun and knockdown of c-Abl and c-Jun expression by small interfering RNA confirmed that adaphostin-induced c-Jun up-regulation triggers downstream caspase-mediated c-Abl cleavage, inhibition of MM cell growth, and induction of apoptosis. Finally, our data suggest that this mechanism may not only be restricted to MM but may also be important in a broad range of malignancies including erythroleukemia and solid tumors. [Cancer Res 2007;67(4):1680–8]

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