Nur77 suppression facilitates androgen deprivation-induced cell invasion of prostate cancer cells mediated by TGF-β signaling
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.
KeywordsProstate cancer Androgen receptor Nur77 Androgen deprivation Cancer cell invasion
We thank the team of Urology Department of Nanjing First Hospital for the technical support in the whole research project.
WJ and SX designed the study, performed the experiments and drafted the manuscript. SX and SH revised the study protocol, supervised the whole project and revised the final draft. YX verified the analytical methods and made the revised draft.
This work was funded by Nanjing Medical Science and Technology Development Program (Serial No. ykk15904 to WJ).
Compliance with ethical standards
Conflict of interest
All authors agreed that there is nothing to disclose for the current study.
The study protocol was approved by the Ethical Committee of Nanjing First Hospital in accordance with the Helsinki Declaration of 1975.
Patients were provided written informed consent prior to be enrolled into the study.
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