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Blood, 12 February 2009, Vol. 113, No. 7, pp. 1513-1521. Prepublished online as a Blood First Edition Paper on November 18, 2008; DOI 10.1182/blood-2008-05-157040. This Article Full Text Full Text (PDF) Supplemental Table and Figures All Versions of this Article: blood-2008-05-157040v1 113/7/1513    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 Raab, M. S. Articles by Podar, K. Search for Related Content PubMed PubMed Citation Articles by Raab, M. S. Articles by Podar, K. Related Collections Myeloid Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  MYELOID NEOPLASIA Targeting PKC: a novel role for beta-catenin in ER stress and apoptotic signaling Marc S. Raab1, Iris Breitkreutz1, Giovanni Tonon2, Jing Zhang1, Patrick J. Hayden1, Thu Nguyen3, Johannes H. Fruehauf3, Boris K. Lin4, Dharminder Chauhan1, Teru Hideshima1, Nikhil C. Munshi1, Kenneth C. Anderson1,*, and Klaus Podar1,* 1 LeBow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center and 2 Center for Applied Cancer Science, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; 3 Skip Ackerman Center for Molecular Therapeutics, Division of Gastroenterology, Beth Israel Medical Center, Harvard Medical School, Boston, MA; and 4 Eli Lilly and Company, Indianapolis, IN Targeting protein kinase C (PKC) isoforms by the small molecule inhibitor enzastaurin has shown promising preclinical activity in a wide range of tumor cells. We further delineated its mechanism of action in multiple myeloma (MM) cells and found a novel role of β-catenin in regulating growth and survival of tumor cells. Specifically, inhibition of PKC leads to rapid accumulation of β-catenin by preventing the phosphorylation required for its proteasomal degradation. Microarray analysis and small-interfering RNA (siRNA)–mediated gene silencing in MM cells revealed that accumulated β-catenin activates early endoplasmic reticulum stress signaling via eIF2, C/EBP-homologous protein (CHOP), and p21, leading to immediate growth inhibition. Furthermore, accumulated β-catenin contributes to enzastaurin-induced cell death. Sequential knockdown of β-catenin, c-Jun, and p73, as well as overexpression of β-catenin or p73 confirmed that accumulated β-catenin triggers c-Jun–dependent induction of p73, thereby conferring MM cell apoptosis. Our data reveal a novel role of β-catenin in endoplasmic reticulum (ER) stress-mediated growth inhibition and a new proapoptotic mechanism triggered by β-catenin on inhibition of PKC isoforms. Moreover, we identify p73 as a potential novel therapeutic target in MM. Based on these and previous data, enzastaurin is currently under clinical investigation in a variety of hematologic malignancies, including MM. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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