Molecular changes that occur during prostate carcinogenesis have partly been attributed to the activation of mediators of inflammation. Prostaglandins that are produced from fatty acids released from membrane lipids by the rate-limiting enzyme cyclooxygenases 1 and 2 may play a significant role in prostate carcinogenesis. Recent evidences suggest that PGE2 stimulation of both EP2 and EP4 receptors involves the transactivation of the epidermal growth factor receptor (EGFR) and thus promote tumorigenesis. Besides the normal function of PGE2 in controlling gastric secretion and renal function, studies indicate that PGE2 may contribute to the tumorigenesis via induction of cell proliferation, angiogenesis, invasion and metastasis. Although PGE2 has been known to elicit its functions through membrane receptors (EP1, EP2, EP3, and EP4), their level of expression in early prostate carcinogenesis is still unclear. While EGFR signaling is another major factor in promoting the molecular events of prostate cancer, phosphorylation of EGFR leads to the activation of down stream signaling molecules involved in survival pathways of the ras/raf/MAPK and PI3K/Akt pathways. However, PGE2, EGF and AR could independently exert their effects on tumor proliferation. In this study, our goal is (a) to investigate whether a moderate level of PGE2 could stimulate EP2 and EP4 receptors (b) to determine whether silencing the expression of EP2 and EP4 will reduce the level of EGFR and AR in prostate cancer cells. To answer the above questions, we are providing findings from cell culture and animal studies involving transgenic adenocarcinoma of the mouse prostate (TRAMP) and MNU/testosterone-induced prostate cancer of the rats. Based on the findings from the dorsolateral prostate tissues examined from both of these animal models, we report the co-existence of varying levels of COX-2, EP2, EP4, EGFR and AR in the tissues of the low-grade mPIN and rat PIN lesions. The tumor cells derived from both of these prostate tissues showed down regulation of EGFR (> 4 fold decrease) in EP2 knock down cells by siRNA. In contrary, androgen independent human PC-3 cells after treatment with siRNA for EP2 showed no changes in the expression of EGFR and/or AKT protein levels, which is determined by Western blot analysis. However, pretreatment of prostate cancer cells including PC-3 cells with COX-2 inhibitor showed a significant decrease in the EP2 protein and total and phosphorylated (Tyr 992) EGFR and AKT (ser-473) proteins associated with tumor cell growth inhibition (65%) and apoptosis (36%). These findings suggest that pretreatment with COX-2 inhibitors is necessary to down regulate EP2 and/or EP4 and thus inhibit the transctivation of EGFR and the AKT signaling pathways involved in androgen-independent prostate cancer (Supported by NIH/NCI CA106296-01, and CA107813-01 grants).

99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA