Transcription factor signal transducer and activator of transcription 5 promotes growth of human prostate cancer cells in vivo
Transcription factor signal transducer and activator of transcription 5 promotes growth of human prostate cancer cells in vivo
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DOI：
10.1158/1078-0432.ccr-07-2024
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发表时间：
2008-03-01
影响因子：
11.5
通讯作者：
Nevalainen, Marja T.
中科院分区：
文献类型：
--
作者：
Dagvadorj, Ayush;Kirken, Robert A.;Nevalainen, Marja T.
目的：信号转导器和转录激活剂 5a/b (Stat5a/b) 是通过激活 Janus 激活激酶 2 在前列腺癌细胞中发挥催乳素作用的关键介质。催乳素是人类前列腺癌中局部产生的生长因子。催乳素蛋白表达和 Stat5a/b 的组成性激活与临床前列腺癌的高组织学分级相关。此外，原发性前列腺癌中 Stat5a/b 的激活可预测早期疾病复发。在这里，我们通过几种不同的方法抑制 Stat5a/b。我们的目标是建立一个原理证明，证明 Stat5a/b 对于体外前列腺癌细胞活力和体内前列腺肿瘤生长至关重要。 实验设计：我们通过反义寡核苷酸或 RNA 干扰抑制 Stat5a/b 蛋白表达，并通过培养的前列腺癌细胞中 Stat5a/b 显性失活突变体的腺病毒表达抑制 Stat5a/b 转录活性。此外，Stat5a/b 活性在裸鼠的人前列腺癌异种移植肿瘤中受到抑制。 Stat5a/b 对 Bcl-X-L 和细胞周期蛋白 D1 蛋白水平的调节通过反义抑制 Stat5a/b 蛋白表达并随后进行蛋白质印迹来证明。结果和结论：我们在此表明，通过反义寡核苷酸、RNA 干扰或显性失活 Stat5a/b 的腺病毒表达抑制 Stat5a/b 可有效杀死前列腺癌细胞。此外，我们还发现 Stat5a/b 对于裸鼠体内人类前列腺癌异种移植物的生长至关重要。 Stat5a/b 对前列腺癌细胞活力的影响涉及 Stat5a/b 对 Bcl-XL 和细胞周期蛋白 D1 蛋白水平的调节，但不涉及 Stat3 的表达或激活。这项工作将 Stat5a/b 确定为前列腺癌的治疗靶蛋白。 Stat5a/b 在前列腺癌中的药理学抑制可以通过 Stat5a/b 反式激活、二聚化或 DNA 结合的小分子抑制剂来实现。
Purpose: Signal transducer and activator of transcription 5a/b (Stat5a/b) is the key mediator of prolactin effects in prostate cancer cells via activation of Janus-activated kinase 2. Prolactin is a locally produced growth factor in human prostate cancer. Prolactin protein expression and constitutive activation of Stat5a/b are associated with high histologic grade of clinical prostate cancer. Moreover, activation of Stat5a/b in primary prostate cancer predicts early disease recurrence. Here, we inhibited Stat5a/b by several different methodologic approaches. Our goal was to establish a proof of principle that Stat5a/b is critical for prostate cancer cell viability in vitro and for prostate tumor growth in vivo.Experimental Design: We inhibited Stat5a/b protein expression by antisense oligonucleotides or RNA interference and transcriptional activity of Stat5a/b by adenoviral expression of a dominant-negative mutant of Stat5a/b in prostate cancer cells in culture. Moreover, Stat5a/b activity was suppressed in human prostate cancer xenograft tumors in nude mice. Stat5a/b regulation of Bcl-X-L and cyclin D1 protein levels was shown by antisense suppression of Stat5a/b protein expression followed by Western blotting.Results and Conclusions: We show here that inhibition of Stat5a/b by antisense oligonucleotides, RNA interference, or adenoviral expression of dominant-negative Stat5a/b effectively kills prostate cancer cells. Moreover, we show that Stat5a/b is critical for human prostate cancer xenograft growth in nude mice. The effects of Stat5a/b on the viability of prostate cancer cells involve Stat5a/b regulation of Bcl-XL and cyclin D1 protein levels but not the expression or activation of Stat3. This work establishes Stat5a/b as a therapeutic target protein for prostate cancer. Pharmacologic inhibition of Stat5a/b in prostate cancer can be achieved by small-molecule inhibitors of transactivation, dimerization, or DNA binding of Stat5a/b.