Development of a small-molecule serum- and glucocorticoid-regulated kinase-1 antagonist and its evaluation as a prostate cancer therapeutic.
Development of a small-molecule serum- and glucocorticoid-regulated kinase-1 antagonist and its evaluation as a prostate cancer therapeutic.
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DOI：
10.1158/0008-5472.can-08-1047
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发表时间：
2008-09-15
期刊：
影响因子：
11.2
通讯作者：
McDonnell DP
中科院分区：
文献类型：
--
作者：
Sherk AB;Frigo DE;Schnackenberg CG;Bray JD;Laping NJ;Trizna W;Hammond M;Patterson JR;Thompson SK;Kazmin D;Norris JD;McDonnell DP
雄激素通过对雄激素受体（AR）的作用，是前列腺发育所必需的，并有助于前列腺癌中观察到的病理性生长失调。因此，雄激素消融已成为前列腺癌药物治疗的重要组成部分。在这项研究中，我们探索了AR下游靶向过程作为替代治疗方法的效用。具体来说，我们证明了血清和糖皮质激素调节的激酶1 （sgk1）基因是前列腺癌细胞模型中雄激素调节的靶基因。此外，通过其靶蛋白Nedd4-2的磷酸化确定的功能性SGK1蛋白也在雄激素治疗中增加。重要的是，我们确定了rnai介导的SGK1表达下调会减弱雄激素介导的前列腺癌细胞系LNCaP的生长。鉴于这些发现，我们通过开发和评估SGK1的小分子抑制剂来探索SGK1作为前列腺癌治疗靶点的效用。从这些研究中出现了GSK650394，一种定量阻断雄激素对LNCaP细胞生长影响的竞争性抑制剂。因此，除了雄激素消融术外，抑制AR下游通路可能对前列腺癌有治疗作用。
Androgens, through their actions on the androgen receptor (AR), are required for the development of the prostate and contribute to the pathological growth dysregulation observed in prostate cancers. Consequently, androgen ablation has become an essential component of the pharmacotherapy of prostate cancer. In this study, we explored the utility of targeting processes downstream of AR as an alternate approach for therapy. Specifically, we demonstrate that the serum and glucocorticoid-regulated kinase 1 (sgk1) gene is an androgen-regulated target gene in cellular models of prostate cancer. Furthermore, functional SGK1 protein, as determined by the phosphorylation of its target Nedd4-2, was also increased with androgen treatment. Importantly, we determined that RNAi-mediated knockdown of SGK1 expression attenuates androgen-mediated growth of the prostate cancer cell line, LNCaP. Given these findings, we explored the utility of SGK1 as a therapeutic target in prostate cancer by developing and evaluating a small molecule inhibitor of this enzyme. From these studies emerged GSK650394, a competitive inhibitor that quantitatively blocks the effect of androgens on LNCaP cell growth. Thus, in addition to androgen ablation, inhibition of pathways downstream of AR are likely to have therapeutic utility in prostate cancer.