Oncogenic RAS mutations in myeloma cells selectively induce cox-2 expression, which participates in enhanced adhesion to fibronectin and chemoresistance

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Abstract
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.