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 3,3′-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 such as AR/PSA, NKX3-1/Akt/p27, MITF, etc. Therefore, isoflavone and BR-DIM with their multi-targeted effects could be useful for the prevention of PCa progression, especially by attenuating bone metastasis mechanisms.
Highlights
Prostate cancer (PCa) is a common cancer and the second leading cause of cancer related deaths in men in the United States with an estimated 241,740 new cases and 28,170 deaths are expected in 2012 [1]
We investigated whether isoflavone mixture G2535 containing 70.5% genistein, and BR-DIM could inhibit the differentiation of osteoclasts and osteoblasts mediated through regulation of cellular signaling pathways that are involved in bone remodeling and PCa bone metastasis
We found that PC-3 prostate cancer cells could grow nicely with pre-osteoclast (Raw264.7) cells (Figure 1A) and that both C4-2B cells and preosteoblasts could grow together (Figure 1B)
Summary
Prostate cancer (PCa) is a common cancer and the second leading cause of cancer related deaths in men in the United States with an estimated 241,740 new cases and 28,170 deaths are expected in 2012 [1]. Targeting osteoblastic molecules such as endothelin-1, BMP, and Wnt signaling has been considered as strategies for inhibiting PCa bone metastasis [2]. Cancer cells could spread to the bone and utilize the local cytokine machinery to stimulate osteoclastogenesis, resulting in bone resorption and cancer cell growth [6]. These findings suggest that bone remodeling including osteolytic and osteoblastic processes occurs during PCa bone metastasis and, in turn, favors the growth of PCa cells in the newly formed bone. Molecular targeting of both osteolytic and osteoblastic mediators would likely inhibit bone remodeling, which could become a newer therapeutic strategy for the inhibition of PCa bone metastasis
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