Tan Shyh-Han, Dagvadorj Ayush, Shen Feng, Gu Lei, Liao Zhiyong, Abdulghani Junaid, Zhang Ying, Gelmann Edward P, Zellweger Tobias, Culig Zoran, Visakorpi Tapio, Bubendorf Lukas, Kirken Robert A, Karras James, Nevalainen Marja T
Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Cancer Res. 2008 Jan 1;68(1):236-48. doi: 10.1158/0008-5472.CAN-07-2972.
The molecular mechanisms underlying progression of prostate cancer to the hormone-independent state are poorly understood. Signal transducer and activator of transcription 5a and 5b (Stat5a/b) is critical for the viability of human prostate cancer cells. We have previously shown that Stat5a/b is constitutively active in high-grade human prostate cancer, but not in normal prostate epithelium. Furthermore, activation of Stat5a/b in primary human prostate cancer predicted early disease recurrence. We show here that transcription factor Stat5a/b is active in 95% of clinical hormone-refractory human prostate cancers. We show for the first time that Stat5a/b synergizes with androgen receptor (AR) in prostate cancer cells. Specifically, active Stat5a/b increases transcriptional activity of AR, and AR, in turn, increases transcriptional activity of Stat5a/b. Liganded AR and active Stat5a/b physically interact in prostate cancer cells and, importantly, enhance nuclear localization of each other. The work presented here provides the first evidence of synergy between AR and the prolactin signaling protein Stat5a/b in human prostate cancer cells.
前列腺癌发展至激素非依赖状态的分子机制目前仍知之甚少。信号转导及转录激活因子5a和5b（Stat5a/b）对人前列腺癌细胞的存活至关重要。我们之前已经表明，Stat5a/b在高级别人前列腺癌中持续激活，但在正常前列腺上皮中则不然。此外，原发性人前列腺癌中Stat5a/b的激活预示着疾病早期复发。我们在此表明，转录因子Stat5a/b在95%的临床激素难治性人前列腺癌中具有活性。我们首次表明，Stat5a/b在前列腺癌细胞中与雄激素受体（AR）协同作用。具体而言，活性Stat5a/b增加AR的转录活性，而AR反过来又增加Stat5a/b的转录活性。配体化的AR与活性Stat5a/b在前列腺癌细胞中发生物理相互作用，重要的是，它们相互增强对方的核定位。本文的研究首次证明了AR与催乳素信号蛋白Stat5a/b在人前列腺癌细胞中的协同作用。
