AKT3 promotes prostate cancer proliferation cells through regulation of Akt, B-Raf, and TSC1/TSC2.
AKT3 promotes prostate cancer proliferation cells through regulation of Akt, B-Raf, and TSC1/TSC2.
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DOI：
10.18632/oncotarget.4553
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发表时间：
2015-09-29
期刊：
影响因子：
--
通讯作者：
Chuu CP
中科院分区：
文献类型：
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作者：
Lin HP;Lin CY;Huo C;Jan YJ;Tseng JC;Jiang SS;Kuo YY;Chen SC;Wang CT;Chan TM;Liou JY;Wang J;Chang WS;Chang CH;Kung HJ;Chuu CP
139例临床样本的qRT-PCR分析和150例在线数据库临床样本的分析表明，原发性前列腺肿瘤中AKT3 mRNA表达水平升高。65例临床标本的免疫组化染色结果显示，AKT3蛋白在I、II、III期前列腺肿瘤中的表达高于邻近正常组织。AKT3的质粒过表达促进LNCaP、PC-3、DU-145和CA-HPV-10人前列腺癌（PCa）细胞的细胞增殖，而通过siRNA敲低AKT3降低细胞增殖。在PC-3 PCa细胞中，AKT3过表达增加了总AKT、磷酸化AKT S473、磷酸化AKT T308、B-Raf、c-Myc、Skp2、细胞周期蛋白E、GSK 3 β、磷酸化GSK 3 β S9、磷酸化mTOR S2448和磷酸化p70 S6 K T421/S424的蛋白表达，但降低了TSC 1（结节性硬化1）和TSC 2（结节性硬化复合物2）蛋白的表达。在LNCaP、DU-145和CA-HPV-10 PCa细胞中，AKT3的过表达也增加了磷酸化AKT S473、磷酸化AKT T308和B-Raf的蛋白丰度，但降低了TSC 1和TSC 2蛋白的表达。Oncomine数据集分析显示，AKT3 mRNA水平与BRAF呈正相关。用siRNA敲低DU-145细胞中的AKT3增加DU-145细胞对B-Raf抑制剂处理的敏感性。TSC1或TSC2的敲除促进PCa细胞的增殖。我们的观察表明AKT3可能是PCa治疗的潜在治疗靶点。
The qRT-PCR analysis of 139 clinical samples and analysis of 150 on-line database clinical samples indicated that AKT3 mRNA expression level was elevated in primary prostate tumors. Immunohistochemical staining of 65 clinical samples revealed that AKT3 protein expression was higher in prostate tumors of stage I, II, III as compared to nearby normal tissues. Plasmid overexpression of AKT3 promoted cell proliferation of LNCaP, PC-3, DU-145, and CA-HPV-10 human prostate cancer (PCa) cells, while knockdown of AKT3 by siRNA reduced cell proliferation. Overexpression of AKT3 increased the protein expression of total AKT, phospho-AKT S473, phospho-AKT T308, B-Raf, c-Myc, Skp2, cyclin E, GSK3β, phospho-GSK3β S9, phospho-mTOR S2448, and phospho-p70S6K T421/S424, but decreased TSC1 (tuberous sclerosis 1) and TSC2 (tuberous Sclerosis Complex 2) proteins in PC-3 PCa cells. Overexpression of AKT3 also increased protein abundance of phospho-AKT S473, phospho-AKT T308, and B-Raf but decreased expression of TSC1 and TSC2 proteins in LNCaP, DU-145, and CA-HPV-10 PCa cells. Oncomine datasets analysis suggested that AKT3 mRNA level was positively correlated to BRAF. Knockdown of AKT3 in DU-145 cells with siRNA increased the sensitivity of DU-145 cells to B-Raf inhibitor treatment. Knockdown of TSC1 or TSC2 promoted the proliferation of PCa cells. Our observations implied that AKT3 may be a potential therapeutic target for PCa treatment.