Mehar Ayaz, Macanas-Pirard Patricia, Mizokami Atsushi, Takahashi Yutaka, Kass Georges E N, Coley Helen M
Postgraduate Medical School, University of Surrey, Guildford, Surrey GU2 7WG, UK.
J Pharmacol Exp Ther. 2008 Mar;324(3):1181-7. doi: 10.1124/jpet.107.131383. Epub 2007 Dec 18.
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 pi (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.
环氧化酶（COX）-2已成为癌症治疗干预中一个令人兴奋的靶点。免疫组织化学研究表明，与良性前列腺组织相比，COX-2在癌组织中的表达更高。我们从凋亡减弱以及对包括COX-2抑制剂在内的药物的敏感性方面，探讨了COX-2在前列腺癌中的作用。将人前列腺癌细胞系LNCaP稳定转染COX-2（LNCaPCOX-2），并与空载体对照系（LNCaPneo）进行比较。化学敏感性测试表明，对COX-2抑制剂塞来昔布或舒林酸或VP16的细胞毒性作用的敏感性没有变化。然而，LNCaPCOX-2细胞对卡铂表现出3倍的抗性，与磷脂酰肌醇3激酶抑制剂渥曼青霉素共同孵育可部分逆转这种抗性。与对细胞毒性药物的凋亡反应降低相一致，LNCaPCOX-2细胞中生存素和Bcl-2的表达水平升高，AKT的激活增强。我们还使用定量聚合酶链反应分析，研究了塞来昔布对我们模型系统中与前列腺癌和耐药性相关基因表达水平的影响。与LNCaPneo细胞相比，塞来昔布处理导致LNCaPCOX-2细胞系中平滑肌成分结蛋白、解毒酶谷胱甘肽S-转移酶pi（GSTpi）和非甾体抗炎反应基因（NAG-1）的mRNA表达显著增加。生存素水平的显著降低以及GSTpi和NAG-1的增加似乎是COX-2依赖性效应，因为它们在LNCaPCOX-2细胞中更为明显。我们的研究结果表明，塞来昔布存在COX-2依赖性和非依赖性机制，并支持其在前列腺癌治疗中的应用。
