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

Wei Meng Xue, Sun Hee Lee, 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, Scott H. Kaufmann

Research output: Contribution to journalArticle

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-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) asparticacid(O-methylester)-fluoromethylketone (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.

Original languageEnglish (US)
Pages (from-to)29831-29846
Number of pages16
JournalJournal of Biological Chemistry
Volume282
Issue number41
DOIs
StatePublished - Oct 12 2007

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Xue, W. M., Lee, S. H., Dai, H., Loegering, D., Yu, C., Flatten, K., Schneider, P., Dai, N. T., Kumar, S. K., Smith, B. D., Karp, J. E., Adjei, A. A., & Kaufmann, S. H. (2007). 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. Journal of Biological Chemistry, 282(41), 29831-29846. https://doi.org/10.1074/jbc.M706110200