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CHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

The Effects of Cyclooxygenase-2 Expression in Prostate Cancer Cells: Modulation of Response to Cytotoxic Agents

Oncology Division, Postgraduate Medical School (A.M., P.M.-P., H.M.C.) and School of Biological and Molecular Sciences (G.E.N.K.), University of Surrey, Surrey, United Kingdom; Department of Urology, Kanazawa University, Kanazawa, Japan (A.M.); and Department of Nutritional Science, Faculty of Health and Welfare Science, Okayama Prefectural University, Okayama, Japan (Y.T.)

Cyclooxygenase (COX)-2 has emerged as an exciting target for therapeutic intervention in the management of cancer. Immunohistochemistry studies have indicated higher expression of COX-2 in cancerous versus benign prostatic tissue. We have explored the role of COX-2 in prostate cancer in terms of attenuation of apoptosis and sensitivity to pharmacological agents, including COX-2 inhibitors. The human prostate cancer cell line LNCaP was stably transfected with COX-2 (LNCaPCOX-2) and compared with the empty vector control line (LNCaPneo). Chemosensitivity testing indicated no change in sensitivity to the cytotoxic effects of COX-2 inhibitors celecoxib or sulindac or VP16. However, LNCaPCOX-2 cells showed 3-fold resistance to carboplatin, which was partially reversed by coincubation with the phosphatidylinositol 3-kinase inhibitor wortmannin. Concomitant with reduced apoptotic response to cytotoxic agents, LNCaPCOX-2 cells expressed increased levels of survivin and Bcl-2 with enhanced activation of AKT. We also investigated the effects of celecoxib on expression levels of genes relevant to prostate cancer and drug resistance in our model system using quantitative polymerase chain reaction analysis. Celecoxib treatment resulted in highly significant increases in the mRNA expression of the smooth muscle component desmin, the detoxification enzyme glutathione S-transferase (GSTpi), and nonsteroidal anti-inflammatory response gene (NAG-1) in the LNCaPCOX-2 cell line compared with LNCaPneo cells. Significant decreases in survivin levels and increases in GSTpi and NAG-1 appeared to be COX-2-dependent effects because they were more pronounced in LNCaPCOX-2 cells. Our findings indicate both COX-2-dependent and -independent mechanisms attributable to celecoxib and support its utility in the management of prostate cancer.

Address correspondence to: Dr. Helen M. Coley, Postgraduate Medical School, University of Surrey, Guildford, Surrey GU2 7WG, UK. E-mail: h.coley{at}surrey.ac.uk