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

• Published in: The Journal of biological chemistry 2007-10, Vol.282 (41), p.29831-29846
• Main Authors: Meng, Xue Wei, Lee, Sun-Hee, Dai, Haiming, Loegering, David, Yu, Chunrong, Flatten, Karen, Schneider, Paula, Dai, Nga T, Kumar, Shaji K, Smith, B. Douglas, Karp, Judith E, Adjei, Alex A, Kaufmann, Scott H
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis Regulatory Proteins - metabolism; bcl-2 Homologous Antagonist-Killer Protein - metabolism; Bcl-2-Like Protein 11; bcl-X Protein - metabolism; Benzenesulfonates - pharmacology; BH3 Interacting Domain Death Agonist Protein - biosynthesis; Cell Line, Tumor; HL-60 Cells; Humans; Jurkat Cells; K562 Cells; Membrane Proteins - metabolism; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasm Proteins - physiology; Niacinamide - analogs & derivatives; Phenylurea Compounds; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-bcl-2 - metabolism; Proto-Oncogene Proteins c-bcl-2 - physiology; Pyridines - pharmacology; Sorafenib; TNF-Related Apoptosis-Inducing Ligand - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M706110200

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-α-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-xL as the predominant antiapoptotic Bcl-2 homologs, demonstrated that TRAIL treatment resulted in binding of tBid to Bcl-xL 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-(Nα-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.