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Blood, 15 September 2007, Vol. 110, No. 6, pp. 2092-2101. Prepublished online as a Blood First Edition Paper on May 31, 2007; DOI 10.1182/blood-2007-04-083204. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2007-04-083204v1 110/6/2092    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Pei, X.-Y. Articles by Grant, S. Search for Related Content PubMed PubMed Citation Articles by Pei, X.-Y. Articles by Grant, S. Related Collections Neoplasia Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA MEK1/2 inhibitors potentiate UCN-01 lethality in human multiple myeloma cells through a Bim-dependent mechanism Xin-Yan Pei1, Yun Dai1, Sarah Tenorio1, Jianghua Lu1, Hisashi Harada1, Paul Dent2, and Steven Grant1,3 Departments of1 Medicine 2 Biochemistry, and 3 Pharmacology, Virginia Commonwealth University/Massey Cancer Center, Richmond The role of Bim in synergistic interactions between UCN-01 and MEK1/2 inhibitors in human multiple myeloma cells was investigated. Exposure of U266 or RPMI8226 cells to UCN-01 resulted in ERK1/2 activation-associated BimEL phosphorylation/down-regulation, events abrogated by MEK1/2 inhibitors. Enforced activation of ERK1/2 by transfection with constitutively active MEK1 diminished the capacity of PD98059 but not PD184352 to block UCN-01–mediated BimEL phosphorylation and to potentiate apoptosis. Cotreatment with MEK1/2 inhibitors increased the association of BimEL with both Bcl-2 and Bcl-xL in UCN-01–treated cells, leading to Bax/Bak conformational change and Bax mitochondrial translocation. Down-regulation of BimEL by shRNA substantially diminished UCN-01/MEK inhibitor-mediated Bax/Bak activation and apoptosis. Furthermore, transfection of cells with S65A Bim, a mutant resistant to UCN-01–mediated phosphorylation, significantly sensitized cells to UCN-01 lethality. Conversely, ectopic expression of either Bcl-2 or Bcl-xL did not alter UCN-01/MEK1/2 inhibitor-mediated modifications in BimEL phosphorylation but largely prevented cell death. Finally, IL-6 or IGF-1 failed to prevent MEK1/2 inhibitors from blocking UCN-01–induced BimEL phosphorylation/degradation or cell death. Collectively, these findings argue that UCN-01–mediated ERK1/2 activation leads to BimEL phosphorylation/inactivation, resulting in cytoprotection, and that interference with these events by MEK1/2 inhibitors plays a critical role in synergistic induction of apoptosis by these agents. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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