Nrdp1-Mediated ErbB3 Increase During Androgen Ablation and Its Contribution to Androgen-Independence.

摘要

Despite availability of improved androgen receptor (AR) inhibitors for the treatment of castration-resistant prostate cancer (CRPC), resistance to treatment develops, and has been traced to activation of multiple signaling pathways suppressed by the AR. We previously showed that the AR maintained castration sensitivity in prostate cancer (PCa) by transcriptional regulation of the E3 ubiquitin ligase Nrdp1, which degrades the receptor tyrosine kinase (RTK) ErbB3; whereas AR inhibition suppressed Nrdp1 levels, thereby activating ErbB3. This resulted in CRPC growth and AR stimulation, but in CRPC, the AR was unable to regulate Nrdp1 or suppress ErbB3, causing uncontrolled progression. Here, we investigate the mechanism by which the AR regulates Nrdp1 transcription and why this regulation is lost in CRPC. Immunohistochemical studies in human PCa tissue and in PCa mouse models demonstrated Nrdp1 localization in both nucleus and cytoplasm. In vitro studies determined cytoplasmic Nrdp1 is 36kDa while nuclear Nrdp1 is 28kDa; the 36kDa form, but not the 28kDa form, negatively correlated with ErbB3 levels, but both forms positively correlated with AR. We demonstrate that Nrdp1 is a direct transcriptional target of the AR in androgen-dependent cells expressing a truncated form of the structural protein Filamin A (FlnA) in the nucleus, but in CRPC cells which have lost nuclear FlnA expression, the AR is no longer able to bind to the Nrdp1 promoter. Restoration of nuclear FlnA restored the ability of AR to regulate Nrdp1 transcription. Thus dual targeting of ErbB3 and AR may be effective in patients whose tumors express nuclear FlnA.