Received for publication September 12, 2007.
Revised December 17, 2007.
Accepted for publication December 17, 2007.

The effects of COX-2 expression in prostate cancer cells: modulation of response to cytotoxic agents

Abstract

Cyclooxygenase-2 (COX-2) has emerged as an exciting target for therapeutic intervention in the management of cancer. Immuno-histochemistry 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 co-incubation with the PI-3 kinase inhibitor wortmanin. 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 PCR analysis. Celecoxib treatment resulted in highly significant increases in the mRNA expression of the smooth muscle component desmin, the detoxification enzyme GSTpi and Nonsteroidal-Anti-inflammatory response gene NAG-1 in the LNCaPCOX-2 cell line when compared with LNCaPneo cells. Significant decreases in survivin levels and increases in GST-pi and NAG-1 appeared to be COX-2-dependent effects as 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.

Key words: COX-2, apoptosis, celecoxib, chemosensitivity, gene expression, prostate cancer