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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.
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Submitted October 3, 2005
Accepted January 8, 2006
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*
David Geffen School of Medicine, UCLA, Los Angeles, CA, USA; Greater Los Angeles VA Healthcare System, Los Angeles, CA, USA
David Geffen School of Medicine, UCLA, Los Angeles, CA, USA; Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, CA, USA; Johnson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA
David Geffen School of Medicine, UCLA, Los Angeles, CA, USA; Johnson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA; Greater Los Angeles VA Healthcare System, Los Angeles, CA, USA
* Corresponding author; email: Alan.Lichtenstein{at}med.va.gov.
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 upregulation of COX-2 expression and enhanced secretion of PGE2, a product of COX-2. Furthermore, in three primary marrow specimens, which contained MM cells expressing mutated ras, 15-40% 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.
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