Cronauer M V, Ince Y, Engers R, Rinnab L, Weidemann W, Suschek C V, Burchardt M, Kleinert H, Wiedenmann J, Sies H, Ackermann R, Kröncke K-D
Department of Urology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
Oncogene. 2007 Mar 22;26(13):1875-84. doi: 10.1038/sj.onc.1209984. Epub 2006 Sep 18.
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.
慢性炎症会增加患癌风险，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）是一种在炎症反应中主要表达的酶。尽管在病理生理过程中，如急性或慢性炎症、自身免疫性疾病或肿瘤发生过程中，已证实iNOS可合成大量一氧化氮（NO），但iNOS活性在这些疾病中的作用大多仍未被充分了解。通过免疫组织化学分析前列腺癌活检样本，我们发现肿瘤细胞中iNOS蛋白表达与硝基酪氨酸高度平行，这表明iNOS具有完全活性。在体外，NO以浓度依赖的方式抑制雄激素受体依赖性启动子活性、前列腺特异性抗原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基因构建体活性的抑制既不是由于AR蛋白水平降低，也不是由于其核转运受到抑制。此外，NO抑制雄激素受体阳性前列腺癌细胞增殖的效率明显高于雄激素受体阴性前列腺癌细胞。总之，我们的研究结果表明，肿瘤内iNOS活性有利于雄激素受体非依赖性增殖的前列腺癌细胞的发展，从而促进前列腺肿瘤进展。
