Effect of COX-2 (PGE2) and IL-6 on Prostate Cancer Bone Metastases

Abstract

Abstract : We hypothesized that (1) prostate cancer cells that express high levels of cyclooxygenase-2 (COX-2) and prostaglandin E2(PGE2) display enhanced bone targeting and (2) the level of expression of COX-2 and PGE2 in established bone metastases determines the overall bone response, with lower vs. higher levels inducing osteoblastic vs. osteolytic responses, respectively. We utilized two human prostate cancer cell lines (MDA-PCa-2B that expresses low levels of COX-2 and PGE2 and produces osteoblastic lesions vs. PC-3 that expresses high levels COX-2/PGE2 and induces osteolytic mets). We demonstrated that (1) low levels of PGE2 stimulate preosteoblast cell growth, differentiation and Wnt signaling (2) Forced overexpression of COX-2 in MDA-PCa-2b cells induces the Wnt antagonist DKK-1 (3) PGE2 addition to PC-3 cells stimulates Dkk-1 (4) Forced overexpression of COX-2 in MDA-PCa-2B cells inhibits preosteoblastic cell growth in co-culture and, finally, (5) Treatment with a COX-2 inhibitor reduced PC-3 metastatic lesions in vivo after intracardiac inoculation. Over the next several weeks we will analyze bone metastatic lesions to determine overall bone response in vivo from the PC-3 experiments and from tibia of mice inoculated with wild-type vs. COX-2 overexpressing MDA-PCa-2b cells. These studies confirmed our hypothesis that levels of COX-2/PGE2 expression in prostate cancer cells modulates both bone targeting and bone response.