Pathology, Wayne State University School of Medicine, 740 HWCRC, 4100 John R St, Detroit, MI, 48201, United States.
The development of prostate cancer (PCa) and its progression to castrate-resistant prostate cancer (CRPC) after anti-androgen ablation therapy are driven by persistent biological activity of androgen receptor (AR) signaling. Moreover, studies have shown that more than 50% of human PCa over-express ERG due to AR-regulated TMPRSS2-ERG fusion gene. However, the reported roles of TMPRSS2-ERG fusion in cancer progression are not clear. In this study, we investigated the signal transduction in the AR/TMPRSS2-ERG/Wnt signaling network for studying the aggressive behavior of PCa cells, and further assessed the effects of BR-DIM and CDF (natural agents-derived synthetic formulation and analogue of DIM and curcumin, respectively with improved bioavailability) on the regulation of AR/TMPRSS2-ERG/Wnt signaling. We found that activation of AR resulted in the induction of ERG expression through TMPRSS2-ERG fusion. Moreover, we found that ERG over-expression and nuclear translocation activated the activity of Wnt signaling. Furthermore, forced over-expression of ERG promoted invasive capacity of PCa cells. More importantly, we found that BR-DIM and CDF inhibited the signal transduction in the AR/TMPRSS2-ERG/Wnt signaling network, leading to the inactivation of Wnt signaling consistent with inhibition of PCa cell invasion. In addition, BR-DIM and CDF inhibited proliferation of PCa cells and induced apoptotic cell death. Based on our findings, we conclude that because BR-DIM and CDF down-regulate multiple signaling pathways including AR/TMPRSS2-ERG/Wnt signaling, these agents could be useful for designing novel strategies for the prevention and/or treatment of PCa.
Written by:
Li Y, Kong D, Wang Z, Ahmad A, Bao B, Padhye S, Sarkar FH. Are you the author?
Reference: Cancer Prev Res (Phila). 2011 Jun 16. Epub ahead of print.
doi: 10.1158/1940-6207.CAPR-11-0077
PubMed Abstract
PMID: 21680704
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