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J. Biol. Chem., Vol. 282, Issue 41, 29831-29846, October 12, 2007

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MCL-1 as a Buffer for Proapoptotic BCL-2 Family Members during TRAIL-induced Apoptosis

A MECHANISTIC BASIS FOR SORAFENIB (BAY 43-9006)-INDUCED TRAIL SENSITIZATION^*

Xue Wei Meng¹, Sun-Hee Lee¹, Haiming Dai, David Loegering, Chunrong Yu^¶, Karen Flatten, Paula Schneider, Nga T. Dai, Shaji K. Kumar^||, B. Douglas Smith^**, Judith E. Karp^**, Alex A. Adjei^¶, and Scott H. Kaufmann^||2

From the Divisions of Oncology Research and ^¶Medical Oncology, Department of Oncology, Department of Molecular Pharmacology and Experimental Therapeutics, and ^||Division of Hematology, Department of Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota 55905 and ^**Adult Leukemia Program, Sidney Kimmel Cancer Center at Johns Hopkins Hospital, Baltimore, Maryland 21287

Previous studies have suggested that Mcl-1, an antiapoptotic Bcl-2 homolog that does not exhibit appreciable affinity for the caspase 8-generated C-terminal Bid fragment (tBid), diminishes sensitivity to tumor necrosis factor--related apoptosis-inducing ligand (TRAIL). This study was performed to determine the mechanism by which Mcl-1 confers TRAIL resistance and to evaluate methods for overcoming this resistance. Affinity purification/immunoblotting assays using K562 human leukemia cells, which contain Mcl-1 and Bcl-x_L as the predominant antiapoptotic Bcl-2 homologs, demonstrated that TRAIL treatment resulted in binding of tBid to Bcl-x_L but not Mcl-1. In contrast, TRAIL caused increased binding between Mcl-1 and Bak that was diminished by treatment with the caspase 8 inhibitor N-(N-acetylisoleucylglutamylthreonyl) aspartic acid (O-methyl ester)-fluoromethyl ketone (IETD(OMe)-fmk) or the c-Jun N-terminal kinase inhibitor SP600125. In addition, TRAIL caused increased binding of Bim and Puma to Mcl-1 that was inhibited by IETD(OMe)-fmk but not SP600125. Further experiments demonstrated that down-regulation of Mcl-1 by short hairpin RNA or the kinase inhibitor sorafenib increased TRAIL-induced Bak activation and death ligand-induced apoptosis in a wide variety of neoplastic cell lines as well as clinical acute myelogenous leukemia specimens. Collectively, these observations not only suggest a model in which Mcl-1 confers TRAIL resistance by serving as a buffer for Bak, Bim, and Puma, but also identify sorafenib as a potential modulator of TRAIL sensitivity.

Received for publication, February 14, 2007 , and in revised form, August 10, 2007.

^* This work was supported in part by National Institutes of Health Grant R01 CA69008 (to S. H. K.), an Amgen scholar award (to S. K. K.), and a predoctoral fellowship from the Mayo Foundation for Education and Research (to S.-H. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Division of Oncology Research Guggenheim 1342 C, Mayo Clinic, 200 First St., S.W., Rochester, MN 55905. Tel.: 507-284-8950; Fax: 507-284-3906; E-mail: Kaufmann.scott{at}mayo.edu.

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