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

Oncogene volume 24, pages 6861–6869 (2005)Cite this article

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.

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Abbreviations

ERK:

extracellular signal-regulated kinase

CLL:

chronic lymphocytic leukemia

FBS:

heat-inactivated fetal bovine serum

GFP:

green fluorescent protein

MEK:

mitogen-activated and extracellular signal-regulated kinase

ROS:

reactive oxygen species

shRNA:

short hairpin RNA

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Acknowledgements

We are grateful to Keith C Bible, Neil E Kay, Paul Haluska, Crescent Isham, Andrea McCollum and Edward Sausville for reagents and/or advice. We thank Mrs Raquel Ostby for expert secretarial assistance. This work was supported in part by a Research Scholar Award from the American Cancer Society (AAA) and grants from the National Institutes of Health to GJG (R01 DK59427) and SHK (R01 CA69008).

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Authors and Affiliations

  1. Division of Medical Oncology, Mayo Clinic, 200 First Street. SW, Rochester, 55905, MN, USA

    Chunrong Yu, Laura M Bruzek, Xue Wei Meng, Scott H Kaufmann & Alex A Adjei

  2. Department of Medicine, Mayo Clinic, Rochester, 55905, MN, USA

    Gregory J Gores & Scott H Kaufmann

  3. Bayer HealthCare, 400 Morgan Lane, West Haven, 06516, CT, USA

    Christopher A Carter

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  1. Chunrong Yu
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Correspondence to Alex A Adjei.

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Yu, C., Bruzek, L., Meng, X. et al. The role of Mcl-1 downregulation in the proapoptotic activity of the multikinase inhibitor BAY 43-9006. Oncogene 24, 6861–6869 (2005). https://doi.org/10.1038/sj.onc.1208841

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