The role of Mcl-1 downregulation in the proapoptotic activity of the multikinase inhibitor BAY 43-9006

Chunrong Yu, Laura M. Bruzek, Wei Meng Xue, Gregory J. Gores, Christopher A. Carter, Scott H. Kaufmann, Alex A. Adjei

Research output: Contribution to journalArticle

232 Scopus citations

Abstract

BAY 43-9006, a multikinase inhibitor that targets Raf, prevents tumor cell proliferation in vitro and inhibits diverse human tumor xenografts in vivo. The mechanism of action of BAY 43-9006 remains incompletely defined. In the present study, the effects of BAY 43-9006 on the antiapoptotic Bcl-2 family member Mcl-1 were examined. Treatment of A549 lung cancer cells with BAY 43-9006 diminished Mcl-1 levels in a time- and dose-dependent manner without affecting other Bcl-2 family members. Similar BAY 43-9006-induced Mcl-1 downregulation was observed in ACHN (renal cell), HT-29 (colon), MDA-MB-231 (breast), KMCH (cholangiocarcinoma), Jurkat (acute T-cell leukemia), K562 (chronic myelogenous leukemia) and MEC-2 (chronic lymphocytic leukemia) cells. Mcl-1 mRNA levels did not change in BAY 43-9006-treated cells. Instead, BAY 43-9006 enhanced proteasome-mediated Mcl-1 degradation. This Mcl-1 downregulation was followed by mitochondrial cytochrome c release and caspase activation as well as enhanced sensitivity to other proapoptotic agents. The caspase inhibitor Boc-D-fmk inhibited BAY 43-9006-induced caspase activation but not cytochrome c release. In contrast, Mcl-1 overexpression inhibited cytochrome c release and other features of BAY 43-9006-induced apoptosis. Conversely, Mcl-1 downregulation by short hairpin RNA enhanced BAY 43-9006-induced apoptosis. Collectively, these findings demonstrate that drug-induced Mcl-1 downregulation contributes to the proapoptotic effects of BAY 43-9006.

Original languageEnglish (US)
Pages (from-to)6861-6869
Number of pages9
JournalOncogene
Volume24
Issue number46
DOIs
StatePublished - Oct 20 2005

Keywords

  • Adaphostin
  • Apoptosis
  • BAY 43-9006 (sorafenib)
  • MEK
  • Mcl-1
  • Raf

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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