title: Inactivation of AR/TMPRSS2-ERG/Wnt signaling networks attenuates the aggressive behavior of prostate cancer cells.
abstract: The development of prostate cancer and its progression to castrate-resistant prostate cancer (CRPC) after antiandrogen ablation therapy are driven by persistent biological activity of androgen receptor (AR) signaling. Moreover, studies have shown that more than 50% of human prostate cancers overexpress ERG (v-ets avian erythroblastosis virus E26 oncogene related gene) 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 prostate cancer cells and further assessed the effects of BR-DIM and CDF [natural agents-derived synthetic formulation and analogue of 3,3'-diindolylmethane (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 overexpression and nuclear translocation activated the activity of Wnt signaling. Furthermore, forced overexpression of ERG promoted invasive capacity of prostate cancer cells. More important, 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 prostate cancer cell invasion. In addition, BR-DIM and CDF inhibited proliferation of prostate cancer cells and induced apoptotic cell death. On the basis of our findings, we conclude that because BR-DIM and CDF downregulate 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 prostate cancer.
authors.affiliation: Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Li
authors.forename: Dejuan
authors.initials: D
authors.lastname: Kong
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Wang
authors.forename: Aamir
authors.initials: A
authors.lastname: Ahmad
authors.forename: Bin
authors.initials: B
authors.lastname: Bao
authors.forename: Subhash
authors.initials: S
authors.lastname: Padhye
authors.forename: Fazlul H
authors.initials: FH
authors.lastname: Sarkar
mesh_terms: D017209:Apoptosis; D001682:Biological Availability; D049109:Cell Proliferation; D003593:Cytoplasm / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000517:prevention & control*; D011944:Receptors, Androgen / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D000071230:Transcriptional Regulator ERG; D014162:Transfection; D051153:Wnt Proteins / Q000378:metabolism*
chemical_list: C072312:ERG protein, human; D011944:Receptors, Androgen; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D051153:Wnt Proteins; D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human