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Originally published In Press as doi:10.1074/jbc.M506551200 on August 23, 2005 Originally published In Press as doi:10.1074/jbc.M506551200 on August 23, 2005 Originally published In Press as doi:10.1074/jbc.M506551200 on August 18, 2005

J. Biol. Chem., Vol. 280, Issue 42, 35217-35227, October 21, 2005
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Apoptosis Induced by the Kinase Inhibitor BAY 43-9006 in Human Leukemia Cells Involves Down-regulation of Mcl-1 through Inhibition of Translation*

Mohamed Rahmani{ddagger}, Eric Maynard Davis{ddagger}, Cheryl Bauer{ddagger}, Paul Dent§, and Steven Grant{ddagger}§¶1

From the Departments of {ddagger}Medicine, §Biochemistry, and Pharmacology, Virginia Commonwealth University, School of Medicine, Richmond, Virginia 23298

BAY 43-9006 is a kinase inhibitor that induces apoptosis in a variety of tumor cells. Here we report that treatment with BAY 43-9006 results in marked cytochrome c and AIF release into the cytosol, caspase-9, -8, -7, and -3 activation, and apoptosis in human leukemia cells (U937, Jurkat, and K562). Pronounced apoptosis was also observed in blasts from patients with acute myeloid leukemia. These events were accompanied by ERK1/2 inactivation and caspase-independent down-regulation of Mcl-1. Inducible expression of a constitutively active MEK1 construct did not prevent Mcl-1 down-regulation, suggesting that this event is not related to MEK/ERK pathway inactivation. Furthermore, BAY 43-9006 did not induce major changes in Mcl-1 mRNA levels monitored by real-time PCR or Mcl-1 promoter activity demonstrated by luciferase reporter assays, but it did enhance Mcl-1 down-regulation in actinomycin D-treated cells. Inhibition of protein synthesis by cycloheximide or proteasome function with MG132 and pulse-chase studies with [35S]methionine demonstrated that BAY 43-9006 did not diminish Mcl-1 protein stability, nor did it enhance Mcl-1 ubiquitination, but instead markedly attenuated Mcl-1 translation in association with the rapid and potent dephosphorylation of the eIF4E translation initiation factor. Finally, ectopic expression of Mcl-1 in leukemic cells markedly inhibited BAY 43-9006-mediated cytochrome c cytosolic release, caspase-9, -7, and -3 activation, as well as cell death, indicating that Mcl-1 operates upstream of cytochrome c release and caspase activation. Together, these findings demonstrate that BAY 43-9006 mediates cell death in human leukemia cells, at least in part, through down-regulation of Mcl-1 via inhibition of translation.

Received for publication, June 16, 2005 , and in revised form, August 15, 2005.

* This work was supported by Public Health Service Grants CA-63753, CA-93738, CA-100866, and CA-88906 from NCI, National Institutes of Health (NIH), Grant DK52825 from NIH, Award 6045-03 from the Leukemia and Lymphoma Society of America, Award DAMD 17-03-1-0209 from the Department of Defense, and a Translational Research award from the V-foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 To whom correspondence should be addressed: Division of Hematology/Oncology, MCV Station Box 230, VA Commonwealth University, Richmond, VA 23298. Tel.: 804-828-5211; Fax: 804-828-8079; E-mail: stgrant{at}hsc.vcu.edu.


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