targeting bone remodeling by isoflavone and 3,3′-diindolylmethane in the context of prostate cancer bone metastasis针对骨重塑的异黄酮和3、3u2032-diindolylmethane在前列腺癌骨转移的背景下.pdf

Targeting Bone Remodeling by Isoflavone and 3,3 9- Diindolylmethane in the Context of Prostate Cancer Bone Metastasis 1 1 1 1 1,2 Yiwei Li , Dejuan Kong , Aamir Ahmad , Bin Bao , Fazlul H. Sarkar * 1 Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, United States of America, 2 Department of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, United States of America Abstract Prostate cancer (PCa) bone metastases have long been believed to be osteoblastic because of bone remodeling leading to the formation of new bone. However, recent studies have shown increased osteolytic activity in the beginning stages of PCa bone metastases, suggesting that targeting both osteolytic and osteoblastic mediators would likely inhibit bone remodeling and PCa bone metastasis. In this study, we found that PCa cells could stimulate differentiation of osteoclasts and osteoblasts through the up-regulation of RANKL, RUNX2 and osteopontin, promoting bone remodeling. Interestingly, we found that formulated isoflavone and 3,39-diindolylmethane (BR-DIM) were able to inhibit the differentiation of osteoclasts and osteoblasts through the inhibition of cell signal transduction in RANKL, osteoblastic, and PCa cell signaling. Moreover, we found that isoflavone and BR-DIM down-regulated the expression of miR-92a, which is known to be associated with RANKL signaling, EMT and cancer progression. By pathway and network analysis, we also observed the regulatory effects of isoflavone and BR-DIM on multiple signaling pathways s