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题名:Nitric oxide-mediated inhibition of androgen receptor activity: possible implications for prostate cancer progression
作者:M V Cronauer, Y Ince, R Engers, L Rinnab, W Weidemann, C V Suschek, M Burchardt, H Kleinert, J Wiedenmann, H Sies, R Ackermann, K-D Kr??ncke
来源:Oncogene 26[IF=6.872], 1875 - 1884 (22 Mar 2007) Original Article
URL :http://dx.doi.org/10.1038/sj.onc.1209984
日期:070415
摘要: M V Cronauer1,2, Y Ince3, R Engers4, L Rinnab5, W Weidemann2, C V Suschek6,8, M Burchardt1,9, H Kleinert7, J Wiedenmann2, H Sies3, R Ackermann1 and K-D Kr?ncke3

1Department of Urology, Heinrich-Heine-University Dsseldorf, Dsseldorf, Germany
2Department of General Zoology and Endocrinology, University Ulm, Ulm, Germany
3Institute of Biochemistry and Molecular Biology I, Heinrich-Heine-University Dsseldorf, Dsseldorf, Germany
4Institute of Pathology, Heinrich-Heine-University Dsseldorf, Dsseldorf, Germany
5Department of Urology and Pediatric Urology, University Ulm, Ulm, Germany
6Institute of Biochemistry and Molecular Biology II, Heinrich-Heine-University Dsseldorf, Dsseldorf, Germany
7Department of Pharmacology, Johannes Gutenberg University, Mainz, Germany

Correspondence: Dr K-D Kr?ncke, Institute of Biochemistry and Molecular Biology I, Heinrich-Heine-University Dsseldorf, Universit?tsstr. 1, 40225 Dsseldorf, Germany. E-mail: kroencke@uni-duesseldorf.de

8Current address: Department of Plastic and Reconstructive Surgery, Hand Surgery, and Burn Center, University Hospital of the RWTH-Aachen, 52057 Aachen, Germany.

9Current address: Department of Urology and Pediatric Urology, Hannover Medical School, 30625 Hannover, Germany.

Received 7 March 2006; Revised 12 July 2006; Accepted 3 August 2006; Published online 18 September 2006.

Abstract

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.

Keywords: androgen receptor, nitric oxide, prostate cancer, prostate specific antigen, zinc-finger 5ku 1.

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