title: 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.
abstract: 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-alpha-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(alpha)-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.
authors: Divisions of Oncology Research, Department of Oncology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors: Xue Wei
authors: XW
authors: Meng
authors: Sun-Hee
authors: SH
authors: Lee
authors: Haiming
authors: H
authors: Dai
authors: David
authors: D
authors: Loegering
authors: Chunrong
authors: C
authors: Yu
authors: Karen
authors: K
authors: Flatten
authors: Paula
authors: P
authors: Schneider
authors: Nga T
authors: NT
authors: Dai
authors: Shaji K
authors: SK
authors: Kumar
authors: B Douglas
authors: BD
authors: Smith
authors: Judith E
authors: JE
authors: Karp
authors: Alex A
authors: AA
authors: Adjei
authors: Scott H
authors: SH
authors: Kaufmann
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000096:biosynthesis; D000072224:Bcl-2-Like Protein 11; D001557:Benzenesulfonates / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018922:HL-60 Cells; D006801:Humans; D019169:Jurkat Cells; D020014:K562 Cells; D008565:Membrane Proteins / Q000378:metabolism*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000502:physiology*; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism* / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology*; D000077157:Sorafenib; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism*; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C494772:BAK1 protein, human; C438378:BBC3 protein, human; C000606775:BCL2L11 protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; D000072224:Bcl-2-Like Protein 11; D001557:Benzenesulfonates; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D010671:Phenylurea Compounds; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011725:Pyridines; D053221:TNF-Related Apoptosis-Inducing Ligand; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein; D009536:Niacinamide; D000077157:Sorafenib