Inactivation of AR/TMPRSS2-ERG/Wnt signaling networks attenuates the aggressive behavior of prostate cancer cells.
Inactivation of AR/TMPRSS2-ERG/Wnt signaling networks attenuates the aggressive behavior of prostate cancer cells.
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DOI：
10.1158/1940-6207.capr-11-0077
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发表时间：
2011-09
期刊：
影响因子：
--
通讯作者：
Sarkar FH
中科院分区：
文献类型：
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作者：
Li Y;Kong D;Wang Z;Ahmad A;Bao B;Padhye S;Sarkar FH
前列腺癌（PCa）的发展及其在抗雄激素消融治疗后进展为去势抵抗性前列腺癌（CRPC）是由雄激素受体（AR）信号传导的持续生物活性驱动的。此外，研究表明，由于 AR 调节的 TMPRSS2-ERG 融合基因，超过 50% 的人类 PCa 过度表达 ERG。然而，TMPRSS2-ERG 融合在癌症进展中的作用尚不清楚。在本研究中，我们研究了AR/TMPRSS2-ERG/Wnt信号网络中的信号转导，以研究PCa细胞的侵袭行为，并进一步评估了BR-DIM和CDF（天然药物衍生的合成制剂以及DIM和姜黄素的类似物，分别具有改善的生物利用度）对AR/TMPRSS2-ERG/Wnt信号传导的调节作用。我们发现 AR 的激活导致通过 TMPRSS2-ERG 融合诱导 ERG 表达。此外，我们发现ERG过度表达和核转位激活了Wnt信号传导的活性。此外，ERG的强制过度表达促进PCa细胞的侵袭能力。更重要的是，我们发现BR-DIM和CDF抑制AR/TMPRSS2-ERG/Wnt信号网络中的信号转导，导致Wnt信号失活，这与抑制PCa细胞侵袭一致。此外，BR-DIM和CDF抑制PCa细胞增殖并诱导细胞凋亡。根据我们的研究结果，我们得出结论，由于 BR-DIM 和 CDF 下调包括 AR/TMPRSS2-ERG/Wnt 信号在内的多种信号通路，这些药物可用于设计预防和/或治疗 PCa 的新策略。
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.