Nitric oxide-mediated inhibition of androgen receptor activity:: possible implications for prostate cancer progression
Nitric oxide-mediated inhibition of androgen receptor activity:: possible implications for prostate cancer progression
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DOI：
10.1038/sj.onc.1209984
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发表时间：
2007-03-22
期刊：
影响因子：
8
通讯作者：
Kroencke, K.-D.
中科院分区：
文献类型：
--
作者：
Cronauer, M. V.;Ince, Y.;Kroencke, K.-D.
慢性炎症会增加患癌症的风险，许多癌症，包括前列腺癌，都发生在慢性炎症部位。诱导型一氧化氮合酶 (iNOS) 是一种在炎症反应期间主要表达的酶。尽管 iNOS 合成大量一氧化氮 (NO) 已在病理生理过程中得到证实，例如急性或慢性炎症、自身免疫性疾病或肿瘤发生，但 iNOS 活性在大多数这些疾病中的作用仍知之甚少。通过免疫组织化学分析前列腺癌活检，我们发现肿瘤细胞中 iNOS 蛋白的表达与硝基酪氨酸强烈平行，表明 iNOS 完全活跃。在体外，NO 以浓度依赖性方式抑制雄激素受体依赖性启动子活性和前列腺特异性抗原的产生以及雄激素受体 (AR) 的 DNA 结合活性。雄激素受体依赖性报告构建体活性的抑制既不是由于 AR 蛋白水平降低，也不是由于其核输入的抑制。此外，NO对雄激素受体阳性前列腺癌细胞增殖的抑制作用明显比雄激素受体阴性前列腺癌细胞增殖更有效。总之，我们的研究结果表明，肿瘤内 iNOS 活性有利于能够独立于雄激素受体增殖的前列腺癌细胞的发育，从而促进前列腺肿瘤进展。
Chronic inflammation increases the risk of cancer and many cancers, including prostate cancer, arise at sites of chronic inflammation. Inducible nitric oxide synthase ( iNOS) is an enzyme dominantly expressed during inflammatory reactions. Although synthesis of high amounts of nitric oxide (NO) by iNOS has been demonstrated in pathophysiological processes, such as acute or chronic inflammation, autoimmune diseases or tumorigenesis, the role of iNOS activity in most of these diseases is poorly understood. Analysing prostate cancer biopsies by immunohistochemistry we found iNOS protein expression in tumor cells strongly paralleled by nitrotyrosine suggesting that iNOS is fully active. In vitro, NO inhibits androgen receptor-dependent promoter activity and prostate specific antigen production as well as DNA-binding activity of the androgen receptor (AR) in a concentration-dependent manner. Inhibition of the activity of androgen receptor-dependent reporter constructs is neither owing to diminished AR protein levels nor owing to an inhibition of its nuclear import. In addition, NO inhibits the proliferation of androgen receptor-positive prostate cancer cells significantly more efficiently than proliferation of androgen receptor-negative prostate cancer cells. In summary, our findings suggest that intratumoral iNOS activity favors development of prostate cancer cells that are able to proliferate androgen receptor-independently, thereby promoting prostate tumor progression.