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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 (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 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 HighWire 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  |  Next Article  Submitted May 24, 2008 Accepted June 27, 2008 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 Dai, Shuang Chen, Xin-Yan Pei, Jorge A Almenara, Lora B Kramer, Charis A Venditti, Paul Dent, and Steven Grant* Department of Medicine, Virginia Commonwealth University/Massey Cancer Center, Richmond, Virginia, United States Department of Pharmacology, Virginia Commonwealth University/Massey Cancer Center, Richmond, Virginia, United States Department of Biochemistry, Virginia Commonwealth University/Massey Cancer Center, Richmond, Virginia, United States * Corresponding author; email: stgrant{at}vcu.edu. 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 signaling events by pharmacologic (eg, the farnesyltransferase inhibitor R115777 or the MEK1/2 inhibitor PD184352) or genetic means (eg, transfection with dominant-negative Ras or MEK1 shRNA) 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 also 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, co-administration of R115777 diminished Chk1 inhibitor-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? This article has been cited by other articles: B. Dai, X. F. Zhao, P. Hagner, P. Shapiro, K. Mazan-Mamczarz, S. Zhao, Y. Natkunam, and R. B. Gartenhaus Extracellular Signal-Regulated Kinase Positively Regulates the Oncogenic Activity of MCT-1 in Diffuse Large B-Cell Lymphoma Cancer Res., October 1, 2009; 69(19): 7835 - 7843. [Abstract] [Full Text] [PDF]

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