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首页> 外文期刊>International Journal of Cancer =: Journal International du Cancer >Knockdown of the cochaperone SGTA results in the suppression of androgen and PI3K/Akt signaling and inhibition of prostate cancer cell proliferation
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Knockdown of the cochaperone SGTA results in the suppression of androgen and PI3K/Akt signaling and inhibition of prostate cancer cell proliferation

机译：陪伴蛋白SGTA的抑制导致雄激素和PI3K / Akt信号的抑制和前列腺癌细胞增殖的抑制

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摘要

Solid tumors have an increased reliance on Hsp70/Hsp90 molecular chaperones for proliferation, survival and maintenance of intracellular signaling systems. An underinvestigated component of the chaperone system is the tetratricopeptide repeat (TPR)-containing cochaperone, which coordinates Hsp70/Hsp90 involvement on client proteins as well as having diverse individual actions. A potentially important cochaperone in prostate cancer (PCa) is small glutamine-rich TPR-containing protein alpha (SGTA), which interacts with the androgen receptor (AR) and other critical cancer-related client proteins. In this study, the authors used small interfering RNA coupled with genome-wide expression profiling to investigate the biological significance of SGTA in PCa and its influence on AR signaling. Knockdown of SGTA for 72 hr in PCa C4-2B cells significantly altered expression of >1,900 genes (58% decreased) and reduced cell proliferation (p < 0.05). The regulation of 35% of 5α- dihydrotestosterone (DHT) target genes was affected by SGTA knockdown, with gene-specific effects on basal or DHT-induced expression or both. Pathway analysis revealed a role for SGTA in p53, generic PCa and phosphoinositol kinase (PI3K) signaling pathways; the latter evident by a reduction in PI3K subunit p100β levels and decreased phosphorylated Akt. Immunohistochemical analysis of 64 primary advanced PCa samples showed a significant increase in the AR:SGTA ratio in cancerous lesions compared to patient-matched benign prostatic hyperplasia tissue (p < 0.02). This study not only provides insight into the biological actions of SGTA and its effect on genome-wide AR transcriptional activity and other therapeutically targeted intracellular signaling pathways but also provides evidence for PCa-specific alterations in SGTA expression.
机译：实体瘤对Hsp70 / Hsp90分子伴侣的依赖增加，从而促进细胞内信号系统的增殖，存活和维持。伴侣系统中未充分研究的组分是含有四肽重复（TPR）的伴侣蛋白，其可协调Hsp70 / Hsp90参与客体蛋白的作用，并具有多种多样的个体作用。前列腺癌（PCa）中潜在的重要伴侣蛋白是富含谷氨酰胺的小TPR蛋白质α（SGTA），它与雄激素受体（AR）和其他与癌症相关的重要客体蛋白质相互作用。在这项研究中，作者使用小干扰RNA结合全基因组表达谱来研究SGTA在PCa中的生物学意义及其对AR信号传导的影响。在PCa C4-2B细胞中敲低SGTA 72小时可显着改变1900个基因的表达（降低58％）并减少细胞增殖（p <0.05）。 35％5α-二氢睾丸激素（DHT）靶基因的调节受到SGTA的影响，对基础或DHT诱导的表达或两者都有基因特异性影响。路径分析揭示了SGTA在p53，通用PCa和磷酸肌醇激酶（PI3K）信号通路中的作用。后者可通过PI3K亚基p100β水平的降低和磷酸化Akt的降低来证明。与患者匹配的良性前列腺增生组织相比，对64个主要晚期PCa样品的免疫组织化学分析显示，癌性病变中AR：SGTA的比例显着增加（p <0.02）。这项研究不仅为SGTA的生物学作用及其对全基因组AR转录活性和其他治疗性靶向细胞内信号通路的影响提供了见识，而且还为SGTA表达中PCa特异性改变提供了证据。

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