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Chen-Lin Hsieh^*, Changmeng Cai^*,, Ahmed Giwa, Aaronica Bivins, Shao-Yong Chen, Dina Sabry, Kumara Govardhan

Department of Biological Sciences, University of Toledo, Toledo, Ohio 43606, USA

(Correspondence should be addressed to L Shemshedini; Email: lshemsh{at}utnet.utoledo.edu)

*C-L Hsieh and C Cai contributed equally to this work

C Cai and S-Y Chen are now at Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts, USA

Cellular changes that affect the androgen receptor (AR) can cause prostate cancer to transition from androgen dependent to androgen independent, which is usually lethal. One common change in prostate tumors is overexpression of the AR, which has been shown to lead to androgen-independent growth of prostate cancer cells. This led us to hypothesize that expression of a hyperactive AR would be sufficient for androgen-independent growth of prostate cancer cells. To test this hypothesis, stable lune cancer prostate (LNCaP) cell lines were generated, which express a virion phosphoprotein (VP)16-AR hybrid protein that contains full-length AR fused to the strong viral transcriptional activation domain VP16. This fusion protein elicited as much as a 20-fold stronger transcriptional activity than the natural AR. Stable expression of VP16-AR in LNCaP cells yielded androgen-independent cell proliferation, while under the same growth conditions the parental LNCaP cells exhibited only androgen-dependent growth. These results show that expression of a hyperactive AR is sufficient for androgen-independent growth of prostate cancer cells. To study the molecular basis of this enhanced growth, we measured the expression of soluble guanylyl cyclase-1 (sGC1), a subunit of the sGC, an androgen-regulated gene that has been shown to be involved in prostate cancer cell growth. Interestingly, the expression of sGC1 is androgen independent in VP16-AR-expressing cells, in contrast to its androgen-induced expression in control LNCaP cells. RNA_I-dependent inhibition of sGC1 expression resulted in significantly reduced proliferation of VP16-AR cells, implicating an important role for sGC1 in the androgen-independent growth of these cells.