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Blood, 15 September 2008, Vol. 112, No. 6, pp. 2439-2449. Prepublished online as a Blood First Edition Paper on July 9, 2008; DOI 10.1182/blood-2008-05-159392. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2008-05-159392v1 112/6/2439    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 Dai, Y. Articles by Grant, S. Search for Related Content PubMed PubMed Citation Articles by Dai, Y. Articles by Grant, S. Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Interruption of the Ras/MEK/ERK signaling cascade enhances Chk1 inhibitor–induced DNA damage in vitro and in vivo in human multiple myeloma cells Yun Dai1, Shuang Chen1, Xin-Yan Pei1, Jorge A. Almenara1, Lora B. Kramer1, Charis A. Venditti1, Paul Dent2,3, and Steven Grant1,2,4 Departments of1 Medicine, 2 Pharmacology, 3 Radiation Oncology, and 4 Biochemistry, Virginia Commonwealth University/Massey Cancer Center, Richmond, VA The role of the Ras/MEK/ERK pathway was examined in relation to DNA damage in human multiple myeloma (MM) cells exposed to Chk1 inhibitors in vitro and in vivo. Exposure of various MM cells to marginally toxic concentrations of the Chk1 inhibitors UCN-01 or Chk1i modestly induced DNA damage, accompanied by Ras and ERK1/2 activation. Interruption of these events by pharmacologic (eg, the farnesyltransferase inhibitor R115777 or the MEK1/2 inhibitor PD184352) or genetic (eg, transfection with dominant-negative Ras or MEK1 shRNA) means induced pronounced DNA damage, reflected by increased H2A.X expression/foci formation and by comet assay. Increased DNA damage preceded extensive apoptosis. Notably, similar phenomena were observed in primary CD138+ MM cells. Enforced MEK1/2 activation by B-Raf transfection prevented R115777 but not PD184352 from inactivating ERK1/2 and promoting Chk1 inhibitor–induced H2A.X expression. Finally, coadministration of R115777 diminished UCN-01–mediated ERK1/2 activation and markedly potentiated H2A.X expression in a MM xenograft model, associated with a striking increase in tumor cell apoptosis and growth suppression. Such findings suggest that Ras/MEK/ERK activation opposes whereas its inhibition dramatically promotes Chk1 antagonist–mediated DNA damage. Together, these findings identify a novel mechanism by which agents targeting the Ras/MEK/ERK pathway potentiate Chk1 inhibitor lethality in MM. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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