TMPRSS2-ERG activates NO-cGMP signaling in prostate cancer cells.,Oncogene

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TMPRSS2-ERG activates NO-cGMP signaling in prostate cancer cells.
Oncogene ( IF 6.9 ) Pub Date : 2019-02-04 , DOI: 10.1038/s41388-019-0730-9
Feng Zhou _{1,

2,

3} , Shuai Gao _{2,

3} , Dong Han _{2,

3} , Wanting Han _{2,

3} , Sujun Chen ₄ , Susan Patalano _{2,

3} , Jill A Macoska _{2,

3} , Housheng Hansen He ₄ , Changmeng Cai _{2,

3}

Affiliation

The aberrant activation of the ERG oncogenic pathway due to the TMPRSS2-ERG gene fusion is the major event that contributes to prostate cancer (PCa) development. However, the critical downstream effectors that can be therapeutically targeted remain to be identified. In this study, we have found that the expression of the α1 and β1 subunits of soluble guanylyl cyclase (sGC) was directly and specifically regulated by ERG in vitro and in vivo and was significantly associated with TMPRSS2-ERG fusion in clinical PCa cohorts. sGC is the major mediator of nitric oxide (NO)-cGMP signaling in cells that, upon NO binding, catalyzes the synthesis of cGMP and subsequently activates protein kinase G (PKG). We showed that cGMP synthesis was significantly elevated by ERG in PCa cells, leading to increased PKG activity and cell proliferation. Importantly, we also demonstrated that sGC inhibitor treatment repressed tumor growth in TMPRSS2-ERG-positive PCa xenograft models and can act in synergy with a potent AR antagonist, enzalutamide. This study strongly suggests that targeting NO-cGMP signaling pathways may be a novel therapeutic strategy to treat PCa with TMPRSS2-ERG gene fusion.

中文翻译：

TMPRSS2-ERG 激活前列腺癌细胞中的 NO-cGMP 信号传导。

由于 TMPRSS2-ERG 基因融合导致的 ERG 致癌途径的异常激活是导致前列腺癌 (PCa) 发展的主要事件。然而，可作为治疗靶向的关键下游效应物仍有待确定。在这项研究中，我们发现可溶性鸟苷酸环化酶 (sGC) 的 α1 和 β1 亚基的表达在体外和体内受到 ERG 的直接和特异性调节，并且与临床 PCa 队列中的 TMPRSS2-ERG 融合显着相关。sGC 是细胞中一氧化氮 (NO)-cGMP 信号传导的主要介质，在与 NO 结合后，催化 cGMP 的合成并随后激活蛋白激酶 G (PKG)。我们发现 ERG 在 PCa 细胞中显着提高 cGMP 合成，导致 PKG 活性和细胞增殖增加。重要的，我们还证明了 sGC 抑制剂治疗抑制了 TMPRSS2-ERG 阳性 PCa 异种移植模型中的肿瘤生长，并且可以与有效的 AR 拮抗剂 enzalutamide 协同作用。该研究强烈表明靶向 NO-cGMP 信号通路可能是一种用 TMPRSS2-ERG 基因融合治疗 PCa 的新治疗策略。

更新日期：2019-02-05

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