Androgen regulation of soluble guanylyl cyclaseα1 mediates prostate cancer cell proliferation

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