Chau My N, El Touny Lara H, Jagadeesh Shankar, Banerjee Partha P
Department of Biochemistry and Molecular and Cellular Biology, Medical-Dental Building, Georgetown University Medical Center, 3900 Reservoir Road, NW, Washington, DC 20057, USA.
Carcinogenesis. 2007 Nov;28(11):2282-90. doi: 10.1093/carcin/bgm148. Epub 2007 Jul 5.
Telomerase contributes to the infinite replicative potential of cancer cells by conferring proliferation and survival through the regulation of growth factors and apoptotic proteins. Although it is generally known that the phytoestrogen, genistein, has telomerase-repressing and anti-proliferative effects on various cancer cells at pharmacological concentrations, we report here that physiologically achievable concentrations of genistein enhance telomerase activity, the proliferation of human prostate cancer cells and tumor growth in the transgenic adenocarcinoma mouse prostate model. In determining the mechanism for enhanced telomerase activity, we observed that physiological concentrations of genistein activated signal transducers and activators of transcription 3 (STAT3) both in vitro and in vivo and increased STAT3 binding to the telomerase reverse transcriptase promoter in human prostate cancer cells. These results demonstrate for the first time that physiologically achievable concentrations of genistein enhance telomerase reverse transcriptase transcriptional activity in prostate cancer cells via the activation of STAT3. Consequently, these concentrations of genistein will augment the growth of prostate cancer cells that could be detrimental to individuals with prostate cancer and therefore, caution should be exercised when genistein is considered for chemotherapeutic purposes.
端粒酶通过调节生长因子和凋亡蛋白赋予癌细胞增殖和存活能力，从而有助于癌细胞的无限复制潜能。尽管人们普遍知道植物雌激素染料木黄酮在药理浓度下对各种癌细胞具有端粒酶抑制和抗增殖作用，但我们在此报告，在转基因腺癌小鼠前列腺模型中，生理可达到浓度的染料木黄酮可增强端粒酶活性、人前列腺癌细胞的增殖和肿瘤生长。在确定端粒酶活性增强的机制时，我们观察到生理浓度的染料木黄酮在体外和体内均激活了信号转导和转录激活因子3（STAT3），并增加了STAT3与人前列腺癌细胞中端粒酶逆转录酶启动子的结合。这些结果首次证明，生理可达到浓度的染料木黄酮通过激活STAT3增强前列腺癌细胞中端粒酶逆转录酶的转录活性。因此，这些浓度的染料木黄酮会促进前列腺癌细胞的生长，这可能对前列腺癌患者有害，因此，在考虑将染料木黄酮用于化疗目的时应谨慎行事。
