Oncogenic RAS mutations in myeloma cells selectively induce cox-2 expression, which participates in enhanced adhesion to fibronectin and chemoresistance.
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.
David Geffen School of Medicine, University of California, Los Angeles, USA.
Bao
B
Hoang
Li
L
Zhu
Yijiang
Y
Shi
Patrick
P
Frost
Huajun
H
Yan
Sanjai
S
Sharma
Sherven
S
Sharma
Lee
L
Goodglick
Steven
S
Dubinett
Alan
A
Lichtenstein
D002448:Cell Adhesion / Q000235:genetics*; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000032:analysis / Q000235:genetics*; D015232:Dinoprostone / Q000032:analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005353:Fibronectins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D009101:Multiple Myeloma / Q000235:genetics / Q000473:pathology*; D009154:Mutation; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D017154:Stromal Cells / Q000166:cytology
D005353:Fibronectins; D051546:Cyclooxygenase 2; D016283:Proto-Oncogene Proteins p21(ras); D015232:Dinoprostone