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Blood, 1 June 2006, Vol. 107, No. 11, pp. 4484-4490. Prepublished online as a Blood First Edition Paper on February 23, 2006; DOI 10.1182/blood-2005-09-3926. This Article Full Text Full Text (PDF) All Versions of this Article: 2005-09-3926v1 107/11/4484    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 HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Hoang, B. Articles by Lichtenstein, A. Search for Related Content PubMed PubMed Citation Articles by Hoang, B. Articles by Lichtenstein, A. Related Collections Neoplasia Cell Adhesion and Motility Oncogenes and Tumor Suppressors Gene Expression Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Oncogenic RAS mutations in myeloma cells selectively induce cox-2 expression, which participates in enhanced adhesion to fibronectin and chemoresistance Bao Hoang, Li Zhu, Yijiang Shi, Patrick Frost, Huajun Yan, Sanjai Sharma, Sherven Sharma, Lee Goodglick, Steven Dubinett, and Alan Lichtenstein From the David Geffen School of Medicine, University of California, Los Angeles; and the Department of Pathology and Laboratory Medicine, Johnson Comprehensive Cancer Center, Greater Los Angeles Veterans Affairs Healthcare System, CA. Oncogenic RAS expression occurs in up to 40% of multiple myeloma (MM) cases and correlates with aggressive disease. Since activated RAS induces cyclooxygenase-2 (cox-2) expression in other tumor models, we tested a role for cox-2 in mutant RAS–containing MM cells. We used the ANBL-6 isogenic MM cell lines in which the IL-6–dependent parental line becomes cytokine independent following transfection with mutated N-RAS or K-RAS. Both mutated N-RAS– and K-RAS–expressing ANBL-6 cells demonstrated a selective up-regulation of cox-2 expression and enhanced secretion of PGE2, a product of cox-2. Furthermore, in 3 primary marrow specimens, which contained MM cells expressing mutated RAS, 15% to 40% of tumor cells were positive for cox-2 expression by immunohistochemistry. We used cox-2 inhibitors, NS398 and celecoxib, and neutralizing anti-PGE2 antibody to test whether cox-2/PGE2 was involved in the aggressive phenotype of MM ANBL-6 cells containing mutated RAS. Although these interventions had no effect on IL-6–independent growth or adhesion to marrow stromal cells, they significantly inhibited the enhanced binding of mutant RAS– containing MM cells to fibronectin and the enhanced resistance to melphalan. These results indicate a selective induction of cox-2 in MM cells containing RAS mutations, which results in heightened binding to extracellular matrix protein and chemotherapeutic drug resistance. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: G. Bisping, D. Wenning, M. Kropff, D. Gustavus, C. Muller-Tidow, M. Stelljes, G. Munzert, F. Hilberg, G. J. Roth, M. Stefanic, et al. Bortezomib, Dexamethasone, and Fibroblast Growth Factor Receptor 3-Specific Tyrosine Kinase Inhibitor in t(4;14) Myeloma Clin. Cancer Res., January 15, 2009; 15(2): 520 - 531. [Abstract] [Full Text] [PDF]

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