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

Correspondence: Dr K-D Kröncke, Institute of Biochemistry and Molecular Biology I, Heinrich-Heine-University Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, 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.