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Prostate cancer (PCa) frequently metastasizes to bone, resulting in osteoblastic metastases. We have previously shown that bone morphogenetic proteins (BMPs) promote PCa osteoblastic activity, but upstream inducers of BMP expression in PCa are unknown. Wnts are mediators of osteogenesis. Thus, we investigated a potential role for Wnts in prostate cancer osteoblastic lesions. RT-PCR revealed that the PCa cell line C4-2B, derived from LNCaP cells, expressed multiple Wnts and their receptors. Wnt5a increased BMP4, 6, and 7 mRNA expression in C4-2B cells. Furthermore, Wnt5a activated the BMP 4 and 6 promoters. DKK-1, a Wnt inhibitor, diminished BMP4 and 6 promoter activity in C4-2B cells. Conditioned media (CM) from C4-2B cells induced pro-osteoblastic activity (increased alkaline phosphatase and osteocalcin) in pre-osteoblast cells. DKK-1 diminished partially C4-2B CM-induced pro-osteoblastic activity. In addition to increasing osteoblastogenesis, Wnt5a also increased the invasive ability of C4-2B cell in vitro. This process was blocked partially by DKK-1, or Noggin, a BMP inhibitor. These observations indicate that Wnt5a promotes osteoblastic prostate cancer bone metastases, in part, through induction of BMP activity and their ability to induce osteoblastogenesis and invasion.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA