N-myc-downregulated gene 1 (NDRG1) has potent anticancer effects and inhibits cell growth, survival, metastasis, and angiogenesis. Previous studies suggested that NDRG1 is linked to the androgen signaling network, but this mechanistic relationship is unclear. Considering the crucial role of the androgen receptor (AR) in prostate cancer (PCa) progression, here we examined for the first time the effect of NDRG1 on AR expression, activation, and downstream signaling in LNCaP, 22Rv1, and C4-2B PCa cell types. We demonstrate that NDRG1 effectively promotes interaction of AR with the chaperone HSP90, which in turn stabilizes the AR while decreasing its androgen-mediated activation. The expression of NDRG1 suppressed: (1) AR activation, as measured by p-ARSer213 and p-ARSer81; (2) expression of a major AR transcriptional target, prostate-specific antigen (PSA); and (3) AR transcriptional activity, probably via inhibiting the c-Jun-AR interaction by reducing c-Jun phosphorylation (p-c-JunSer63). NDRG1 was also demonstrated to inhibit multiple key molecules involved in androgen-dependent and -independent signaling (namely EGFR, HER2, HER3, PI3K, STAT3, and NF-κB), which promote the development of castration-resistant prostate cancer. We also identified the cysteine-rich secretory protein/antigen 5/pathogenesis related-1 (CAP) domain of NDRG1 as vital for inhibition of AR activity. Examining NDRG1 and p-NDRG1 in PCa patient specimens revealed a significant negative correlation between NDRG1 and PSA levels in prostatectomy patients that went on to develop metastasis. These results highlight a vital role for NDRG1 in androgen signaling and its potential as a key therapeutic target and biomarker in PCa.

中文翻译：

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转移抑制因子 NDRG1 直接调节前列腺癌中的雄激素受体信号传导。

N-myc 下调基因 1 (NDRG1) 具有有效的抗癌作用并抑制细胞生长、存活、转移和血管生成。以前的研究表明 NDRG1 与雄激素信号网络有关，但这种机制关系尚不清楚。考虑到雄激素受体 (AR) 在前列腺癌 (PCa) 进展中的关键作用，我们首次检测了 NDRG1 对 LNCaP、22Rv1 和 C4-2B PCa 细胞中 AR 表达、激活和下游信号传导的影响类型。我们证明 NDRG1 有效促进 AR 与伴侣 HSP90 的相互作用，从而稳定 AR，同时降低其雄激素介导的活化。NDRG1 的表达受到抑制：（1）AR 激活，由 p-ARSer213 和 p-ARSer81 测量；(2) 主要 AR 转录靶点的表达，前列腺特异性抗原（PSA）；(3) AR 转录活性，可能是通过减少 c-Jun 磷酸化 (pc-JunSer63) 来抑制 c-Jun-AR 相互作用。NDRG1 还被证明可抑制参与雄激素依赖性和非依赖性信号传导的多个关键分子（即 EGFR、HER2、HER3、PI3K、STAT3 和 NF-κB），从而促进去势抵抗性前列腺癌的发展。我们还确定了 NDRG1 的富含半胱氨酸的分泌蛋白/抗原 5/发病机制相关-1 (CAP) 结构域对于抑制 AR 活性至关重要。检查 PCa 患者标本中的 NDRG1 和 p-NDRG1 发现，在继续发展为转移的前列腺切除术患者中，NDRG1 和 PSA 水平之间存在显着的负相关。