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The Crucial Role of Cyclooxygenase-2 in Osteopontin-Induced Protein Kinase C /c-Src/IB Kinase /ß–Dependent Prostate Tumor Progression and Angiogenesis

National Center for Cell Science, Pune, India

Requests for reprints: Gopal C. Kundu, National Center for Cell Science, Pune 411 007, India. Phone: 91-20-25690922 ext. 1103; Fax: 91-20-25692259; E-mail: kundu{at}nccs.res.in.

The regulation of tumor progression towards its malignancy needs the interplay among several cytokines, growth factors, and enzymes, which are controlled in the tumor microenvironment. Here, we report that osteopontin, a small integrin-binding ligand N-linked glycoprotein family of calcified extracellular matrix–associated protein, regulates prostate tumor growth by regulating the expression of cyclooxygenase-2 (COX-2). We have shown that osteopontin stimulates the activation of protein kinase C /nuclear factor–inducing kinase/nuclear factor-B–dependent signaling cascades that induces COX-2 expression, which in turn regulates the prostaglandin E₂ production, matrix metalloproteinase-2 activation, and tumor progression and angiogenesis. We have revealed that suppression of osteopontin-induced COX-2 expression by the nonsteroidal anti-inflammatory drug celecoxib or blocking the EP2 receptor by its blocking antibody resulted in significant inhibition of cell motility and tumor growth and angiogenesis. The data also showed that osteopontin-induced mice PC-3 xenograft exhibits higher tumor load, increased tumor cell infiltration, nuclear polymorphism, and neovascularization. Interestingly, use of celecoxib or anti-EP2 blocking antibody drastically suppressed osteopontin-induced tumor growth that further indicated that suppression of COX-2 or its metabolites could significantly inhibit osteopontin-induced tumor growth. Human clinical prostate cancer specimen analysis also supports our in vitro and animal model studies. Our findings suggest that blockage of osteopontin and/or COX-2 is a promising therapeutic approach for the inhibition of prostate tumor progression and angiogenesis. (Cancer Res 2006; 66(13): 6638-48)

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