1. ¹Department of Biological Sciences, University of Toledo, Toledo, OH, USA
2. ²Department of Medicine, Cancer Biology Program/Hematology-Oncology Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
3. ³Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA

Correspondence: Dr L Shemshedini, Department of Biological Sciences, University of Toledo, Toledo, OH 43606, USA. E-mail: lshemsh@utnet.utoledo.edu

⁴Current address: Harvard Medical School, 330 Brookline Avenue, Boston, MA, USA.

⁵Current address: Medical University of Ohio, 3000 Arlington Avenue, Toledo, OH, USA.

⁶Current address: Johns Hopkins University, 615 North Wolfe St., Baltimore, MD, USA.

Received 10 May 2006; Revised 29 June 2006; Accepted 28 July 2006; Published online 11 September 2006.

Abstract

The growth and progression of prostate cancer are dependent on androgens and androgen receptor (AR), which act by modulating gene expression. Utilizing a gene microarray approach, we have identified the 1-subunit gene of soluble guanylyl cyclase (sGC) as a novel androgen-regulated gene. A heterodimeric cytoplasmic protein composed of one and one subunit, sGC mediates the widespread cellular effects of nitric oxide (NO). We report here that, in prostate cancer cells, androgens stimulate the expression of sGC1. A cloned human sGC1 promoter is activated by androgen in an AR-dependent manner, suggesting that sGC1 may be a direct AR target gene. Disruption of sGC1 expression severely compromises the growth of both androgen-dependent and androgen-independent AR-positive prostate cancer cells. Overexpression of sGC1 alone is sufficient for stimulating prostate cancer cell proliferation. Interestingly, the major growth effect of sGC1 is independent of NO and cyclic guanosine monophosphate, a major mediator of the sGC enzyme. These data strongly suggest that sGC1 acts in prostate cancer via a novel pathway that does not depend on sGC1. Tissue studies show that sGC1 expression is significantly elevated in advanced prostate cancer. Thus, sGC1 may be an important mediator of the procarcinogenic effects of androgens.