Department of Urology, Drum Tower Hospital, Medical School of Nanjing University, 321 Zhongshan Rd, Nanjing, 210008, Jiangsu, China.
Department of Urology, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210000, Jiangsu, China.
Clin Transl Oncol. 2018 Oct;20(10):1302-1313. doi: 10.1007/s12094-018-1862-z. Epub 2018 Mar 28.
Androgen deprivation therapy (ADT) remains a standard treatment for advanced prostate cancers. However, recent studies revealed that while inhibiting the growth of certain types of prostate cancer cells, ADT promotes invasion. In the current study, we explored the effects of Nur77, an orphan nuclear receptor, on prostate cancer cell invasion following ADT.
Androgen receptor (AR) and Nur77 protein expression in patient tissues and cell lines were quantified via ELISA and western blot. The effects of AR-signaling on Nur77 expression were examined. The effects of Nur77 over-expression and knockdown on ADT-induced prostate cancer cell invasion were characterized.
The results showed that AR and Nur77 are both highly expressed in prostate cancers of patients. Nur77 is positively regulated by AR-signaling at transcriptional level in NCI-H660, a widely used prostate cancer cell line. AR antagonists, Casodex and MDV3100 treatment resulted in significant inhibition of prostate cancer cell growth but enhanced cancer cell invasion. Nur77 over-expression blocked invasion-promoting effect of ADT, which is consistent with the down-regulation of MMP9 and Snail protein expression. Further mechanistic investigations showed that Nur77 inhibited transcription of TGF-β target genes (Snail and MMP9), and thereby inhibits TGF-β-mediated prostate cancer cell invasion following androgen antagonism. In addition, our data suggested the nature of this inhibitory effect of Nur77 on TGF-β-signaling is selective, for Smad3-signaling, the classical effector of TGF-β-signaling, was not interrupted by Nur77 over-expression.
Considering the limited success of management of prostate cancer metastasis following ADT, our data strongly suggest that Nur77 regulation could be a promising direction for search of complementary therapeutic strategy on top of classic ADT therapy.
雄激素剥夺疗法（ADT）仍然是治疗晚期前列腺癌的标准疗法。然而，最近的研究表明，虽然 ADT 抑制了某些类型的前列腺癌细胞的生长，但它促进了侵袭。在本研究中，我们探讨了孤儿核受体 Nur77 在 ADT 后前列腺癌细胞侵袭中的作用。
通过 ELISA 和 Western blot 定量检测患者组织和细胞系中的雄激素受体（AR）和 Nur77 蛋白表达。研究了 AR 信号对 Nur77 表达的影响。研究了 Nur77 过表达和敲低对 ADT 诱导的前列腺癌细胞侵袭的影响。
结果表明，AR 和 Nur77 在患者的前列腺癌中均高度表达。在广泛使用的前列腺癌细胞系 NCI-H660 中，AR 信号在转录水平上正向调节 Nur77 的表达。AR 拮抗剂 Casodex 和 MDV3100 治疗导致前列腺癌细胞生长显著抑制，但增强了癌细胞侵袭。Nur77 过表达阻断了 ADT 的促侵袭作用，这与 MMP9 和 Snail 蛋白表达的下调一致。进一步的机制研究表明，Nur77 抑制了 TGF-β 靶基因（Snail 和 MMP9）的转录，从而抑制了雄激素拮抗后 TGF-β 介导的前列腺癌细胞侵袭。此外，我们的数据表明，Nur77 对 TGF-β 信号的这种抑制作用是选择性的，因为 Nur77 过表达不会中断 Smad3 信号，Smad3 信号是 TGF-β 信号的经典效应子。
鉴于 ADT 后前列腺癌转移管理的有限成功，我们的数据强烈表明，Nur77 的调节可能是在经典 ADT 治疗基础上寻求互补治疗策略的一个有前途的方向。
