Prostate cancer (PCa) is the most common malignancy and is the second leading cause of cancer among men globally. Using a kinome‐wide lentiviral small‐hairpin RNA (shRNA) library screen, we identified phosphoinositide‐dependent kinase‐1 (PDPK1) as a potential mediator of cell survival in PCa cells. We showed that knock‐down of endogenous human PDPK1 induced significant tumour‐specific cell death in PCa cells (DU145 and PC3) but not in the normal prostate epithelial cells (RWPE‐1). Further analyses revealed that PDPK1 mediates cancer cell survival predominantly via activation of serum/glucocorticoid‐regulated kinase 3 (SGK3). Knock‐down of endogenous PDPK1 in DU145 and PC3 cells significantly reduced SGK3 phosphorylation while ectopic expression of a constitutively active SGK3 completely abrogated the apoptosis induced by PDPK1. In contrast, no such effect was observed in SGK1 and AKT phosphorylation following PDPK1 knock‐down. Importantly, PDPK1 inhibitors (GSK2334470 and BX‐795) significantly reduced tumour‐specific cell growth and synergized docetaxel sensitivity in PCa cells. In summary, our results demonstrated that PDPK1 mediates PCa cells’ survival through SGK3 signalling and suggest that inactivation of this PDPK1‐SGK3 axis may potentially serve as a novel therapeutic intervention for future treatment of PCa.

中文翻译：

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磷酸肌醇依赖性激酶1（PDPK1）调节血清/糖皮质激素调节的激酶3（SGK3）的前列腺癌细胞存活率。

前列腺癌（PCa）是最常见的恶性肿瘤，是全球男性中第二大致癌原因。使用全基因组慢病毒小发夹RNA（shRNA）文库筛选，我们确定了磷酸肌醇依赖性激酶-1（PDPK1）是PCa细胞中细胞存活的潜在介质。我们证明，敲除内源性人PDPK1会在PCa细胞（DU145和PC3）中诱导明显的肿瘤特异性细胞死亡，而在正常前列腺上皮细胞（RWPE-1）中则不会。进一步的分析表明，PDPK1主要通过激活血清/糖皮质激素调节的激酶3（SGK3）介导癌细胞的存活。敲低DU145和PC3细胞中内源性PDPK1的表达可显着降低SGK3的磷酸化，而组成型活性SGK3的异位表达则完全消除了PDPK1诱导的细胞凋亡。相反，PDPK1敲低后未在SGK1和AKT磷酸化中观察到这种作用。重要的是，PDPK1抑制剂（GSK2334470和BX-795）可显着降低PCa细胞中肿瘤特异性细胞的生长并增强多西他赛的敏感性。总而言之，我们的结果表明PDPK1通过SGK3信号传导介导PCa细胞的存活，并表明该PDPK1-SGK3轴的失活可能会作为PCa未来治疗的新型治疗手段。