Zhang Zhe, Hou Xianzeng, Shao Chen, Li Junjie, Cheng Ji-Xin, Kuang Shihuan, Ahmad Nihal, Ratliff Timothy, Liu Xiaoqi
Department of Biochemistry, Purdue University, West Lafayette, Indiana. State Key Laboratory for Agrobiotechnology and Department of Microbiology, China Agricultural University, Beijing, China.
Department of Biochemistry, Purdue University, West Lafayette, Indiana. Department of Neurosurgery, Qianfoshan Hospital affiliated to Shandong University, Jinan, China.
Cancer Res. 2014 Nov 15;74(22):6635-47. doi: 10.1158/0008-5472.CAN-14-1916. Epub 2014 Sep 24.
Prostate cancer is thought to be driven by oxidative stress, lipid metabolism, androgen receptor (AR) signaling, and activation of the PI3K-AKT-mTOR pathway, but it is uncertain how they may become coordinated during progression to castration-resistant disease that remains incurable. The mitotic kinase polo-like kinase 1 (Plk1) is elevated in prostate cancer, where its expression is linked to tumor grade. Notably, Plk1 signaling and lipid metabolism were identified recently as two of the top five most upregulated pathways in a mouse xenograft model of human prostate cancer. Herein, we show that oxidative stress activates both the PI3K-AKT-mTOR pathway and AR signaling in a Plk1-dependent manner in prostate cells. Inhibition of the PI3K-AKT-mTOR pathway prevented oxidative stress-induced activation of AR signaling. Plk1 modulation also affected cholesteryl ester accumulation in prostate cancer via the SREBP pathway. Finally, Plk1 inhibition enhanced cellular responses to androgen signaling inhibitors (ASI) and overcame ASI resistance in both cultured prostate cancer cells and patient-derived tumor xenografts. Given that activation of AR signaling and the PI3K-AKT-mTOR pathway is sufficient to elevate SREBP-dependent expression of key lipid biosynthesis enzymes in castration-resistant prostate cancer (CRPC), our findings argued that Plk1 activation was responsible for coordinating and driving these processes to promote and sustain the development of this advanced stage of disease. Overall, our results offer a strong mechanistic rationale to evaluate Plk1 inhibitors in combination drug trials to enhance the efficacy of ASIs in CRPC.
前列腺癌被认为是由氧化应激、脂质代谢、雄激素受体（AR）信号传导以及PI3K-AKT-mTOR通路的激活所驱动，但目前尚不清楚在进展为无法治愈的去势抵抗性疾病过程中，它们是如何协同作用的。有丝分裂激酶波罗样激酶1（Plk1）在前列腺癌中表达升高，其表达与肿瘤分级相关。值得注意的是，在人前列腺癌的小鼠异种移植模型中，Plk1信号传导和脂质代谢最近被确定为上调最明显的五大通路中的两个。在此，我们表明氧化应激在前列腺细胞中以Plk1依赖的方式激活PI3K-AKT-mTOR通路和AR信号传导。抑制PI3K-AKT-mTOR通路可阻止氧化应激诱导的AR信号激活。Plk1调节还通过SREBP途径影响前列腺癌中的胆固醇酯积累。最后，Plk1抑制增强了细胞对雄激素信号抑制剂（ASI）的反应，并克服了培养的前列腺癌细胞和患者来源的肿瘤异种移植中的ASI耐药性。鉴于AR信号传导和PI3K-AKT-mTOR通路的激活足以提高去势抵抗性前列腺癌（CRPC）中关键脂质生物合成酶的SREBP依赖性表达，我们的研究结果表明Plk1激活负责协调和驱动这些过程，以促进和维持这种晚期疾病的发展。总体而言，我们的结果为在联合药物试验中评估Plk1抑制剂以提高ASI在CRPC中的疗效提供了强有力的机制依据。
