Park Soo-Yeon, Kim Yun-Jeong, Gao Allen C, Mohler James L, Onate Sergio A, Hidalgo Alejandro A, Ip Clement, Park Eun-Mi, Yoon Sun Young, Park Young-Mee
Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Cancer Res. 2006 May 15;66(10):5121-9. doi: 10.1158/0008-5472.CAN-05-1341.
Recent studies show that prostate cancer cells are able to survive in a hypoxic tumor environment, and the extent of tumor hypoxia correlates with poor clinical outcome. Androgen deprivation, the most common form of prostate cancer therapy, was itself shown to induce a state of transient hypoxia at the microenvironmental level. Because androgen receptor (AR) signaling plays a critical role in prostate cancer, we investigated the effect of hypoxia in regulating AR function. We found that in LNCaP prostate cancer cells, AR binding to the androgen-responsive element (ARE), prostate-specific antigen accumulation, and ARE-reporter gene activity were increased after hypoxia treatment. Hypoxia-enhanced AR function was also observed when AR was exogenously introduced into AR-null DU145 cells. Confocal microscopy and chromatin immunoprecipitation assays showed that AR translocation to the nucleus and AR recruitment to the prostate-specific antigen promoter were facilitated after hypoxia treatment. The AR stimulatory effect seemed to be ligand-dependent because it was abrogated when cells were cultured in an androgen-depleted medium, but was restored with the addition of R1881, a synthetic androgen. The sensitivity of AR activation to R1881 was also increased after hypoxia treatment. Although concentrations of <1 nmol/L R1881 did not induce ARE reporter activity under normoxic conditions, exposure to hypoxia greatly potentiated the AR response to low levels of R1881. Collectively, our results provide compelling evidence that changes in hypoxia/reoxygenation stimulate AR trans-activation and sensitization. The AR-stimulatory effect of an unstable tissue oxygenation milieu of a tumor is likely to contribute to treatment resistance and the emergence of recurrent prostate cancer.
最近的研究表明，前列腺癌细胞能够在缺氧的肿瘤环境中存活，肿瘤缺氧程度与不良临床结果相关。雄激素剥夺是前列腺癌治疗最常见的形式，其本身在微环境水平上可诱导短暂缺氧状态。由于雄激素受体（AR）信号通路在前列腺癌中起关键作用，我们研究了缺氧对AR功能调节的影响。我们发现，在LNCaP前列腺癌细胞中，缺氧处理后AR与雄激素反应元件（ARE）的结合、前列腺特异性抗原的积累以及ARE报告基因活性均增加。当将AR外源导入AR缺失的DU145细胞时，也观察到缺氧增强了AR功能。共聚焦显微镜和染色质免疫沉淀分析表明，缺氧处理后AR易位至细胞核以及AR募集至前列腺特异性抗原启动子的过程得到促进。AR的刺激作用似乎依赖配体，因为当细胞在雄激素缺乏的培养基中培养时该作用被消除，但添加合成雄激素R1881后又恢复。缺氧处理后，AR对R1881激活的敏感性也增加。尽管在常氧条件下浓度<1 nmol/L的R1881不会诱导ARE报告基因活性，但缺氧暴露极大地增强了AR对低水平R1881的反应。总体而言，我们的结果提供了令人信服的证据，即缺氧/复氧变化刺激AR反式激活和致敏。肿瘤不稳定的组织氧合环境对AR的刺激作用可能导致治疗抵抗和复发性前列腺癌的出现。
