Abstract 3374: Prostate cancer bone metastases acquire resistance to androgen deprivation via WNT5A-mediated BMP6 induction

• Published in: Cancer research (Chicago, Ill.) Ill.), 2015-08, Vol.75 (15_Supplement), p.3374-3374
• Main Authors: Lee, Geun Taek, Kwon, Seok Joo, Kim, Isaac Yi
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2015-3374

Prostate cancer (CaP) is the second leading cause of cancer death in American men. Traditional androgen ablation is a first-line therapy in relapsed or metastatic prostate cancer cases, but it is eventually rendered ineffective by the development of castration-resistant prostate cancer (CRPC). Once CRPC develops, treament options include taxol-based chemotherapy and second-line hormonal agents, but these have limited effectiveness. In the present study, we have investigated the role of Bone Morphogenetic Protein-6 (BMP6) in the development of castration resistant prostate cancer (CRPC) in the context of bone metastases. We initially investigated the clinical course of 158 men with advanced CaP who were treated with primary androgen deprivation therapy. To elucidate the underlying mechanism of CRPC in the context of bone metastases, we examined the impact of bone stromal cells on CaP in the absence of androgens using a co-culture model. In these patients, we found that the median time to PSA progression was significantly shorter when bone metastases were present (14 months [95% CI, 10.2-17.8 months] vs. 57 months [95% CI, 19.4-94.6 months]). These results suggest that bone-tumor interactions may accelerate castration resistance. Mechanistically, gene expression analysis using quantitative polymerase chain reaction (Q-PCR) arrays showed a dramatic induction of BMP6 by CaP cell lines in the presence of bone stromal cells. Further studies revealed that WNT5A derived from bone stromal cells induced the expression of BMP6 by CaP cells; BMP6 in turn stimulated cellular proliferation of CaP cells in an androgen-deprived media via a physical interaction between Smad5 and β-catenin. Intracellularly, WNT5A increased BMP6 expression via PKC/NF-κB pathway in CaP cell lines. Taken together, these observations suggest that bone-CaP interaction leads to castration resistance via WNT5A/BMP6 loop. We have herein demonstrated that the bone-CaP interaction promotes resistance to androgen deprivation. At the cellular and molecular level, this castration-resistance is mediated by bone stroma-derived WNT5A that leads to the induction of BMP6; BMP6, in turn, permits CaP cells to proliferate in the absence of androgens by interacting with β-catenin. Targeting WNT5A/BMP6/β-catenin may be a viable therapeutic option in men with CaP skeletal metastases and CRPC. Citation Format: Geun Taek Lee, Seok Joo Kwon, Isaac Yi Kim. Prostate cancer bone metastases acquire resistance to androgen