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This Article Accepted manuscript (PDF) All Versions of this Article: JME-07-0158v1 41/1/13    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Hsieh, C.-L. Articles by Shemshedini, L. Search for Related Content PubMed PubMed Citation Articles by Hsieh, C.-L. Articles by Shemshedini, L.

C Hsieh, Biological Sciences, University of Toledo, Toledo, United States
C Cai, Harvard Medical School, Harvard University, Toledo, United States
A Giwa, Biological Sciences, University of Toledo, Toledo, United States
A Bivins, Biological Sciences, University of Toledo, Toledo, United States
S Chen, Harvard Medical School, Harvard University, Boston, United States
D Sabry, Biological Sciences, University of Toledo, Toledo, United States
K Govardhan, Biological Sciences, University of Toledo, Toledo, United States
L Shemshedini, Department of Biological Sciences, University of Toledo, Toledo, 43606, United States

Correspondence: Lirim Shemshedini, Email: lshemsh{at}uoft02.utoledo.edu

Abstract

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 over-expression 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 LNCaP cell lines were generated that express a VP16-AR hybrid protein, which contains full-length AR fused to the strong viral transcriptional activation domain VP16. This fusion protein elicited a 10-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 sGCalpha1, a subunit of the soluble guanylyl cyclase, an androgen-regulated gene that has been shown to be involved in prostate cancer cell growth. Interestingly, the expression of sGCalpha1 is androgen-independent in VP16-AR-expressing cells, in contrast to its androgen-induced expression in control LNCaP cells. RNAI-dependent inhibition of sGCalpha1 expression resulted in significantly reduced proliferation of VP16-AR cells, implicating an important role for sGCalpha1 in the androgen-independent growth of these cells.