This Article Full Text Full Text (PDF) 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 Verras, M. Articles by Sun, Z. Search for Related Content PubMed PubMed Citation Articles by Verras, M. Articles by Sun, Z.

The Androgen Receptor Negatively Regulates the Expression of c-Met: Implications for a Novel Mechanism of Prostate Cancer Progression

¹ Departments of Urology and Genetics, Stanford University School of Medicine, Stanford, California and ² Department of Cancer Endocrinology, BC Cancer Agency, Vancouver, British Columbia, Canada

Requests for reprints: Zijie Sun, Departments of Urology and Genetics, S287, Grant Building, Stanford University School of Medicine, Stanford, CA 94305-5328. Phone: 650-498-7523; Fax: 650-725-8502; E-mail: zsun{at}stanford.edu.

The precise molecular mechanisms by which prostate cancer cells progress from androgen-sensitive to androgen-insensitive status still remain largely unclear. The hepatocyte growth factor/scatter factor (HGF/SF) plays a critical role in the regulation of cell growth, cell motility, morphogenesis, and angiogenesis. The aberrant expression of HGF/SF and its receptor, c-Met, often correlates with poor prognosis in a variety of human malignancies, including prostate cancer. Here, we investigate a potential link between androgen signaling and c-Met expression in prostate cancer cells. First, we showed that the androgen receptor (AR) represses the expression of c-Met in a ligand-dependent manner. Using different c-Met promoter/reporter constructs, we identified that Sp1 induces the transcription of c-Met and that AR can repress the Sp1-induced transcription in prostate cancer cells. Moreover, the data from electrophoretic mobility shift assay showed that AR interferes with the interaction between Sp1 and the functional Sp1 binding site within the c-Met promoter. Furthermore, we tested the effect of AR on c-Met expression in an androgen-insensitive prostate cancer cell line, CWR22Rv1. Finally, the repressive role of androgen signaling on c-Met expression was confirmed in prostate cancer xenografts. The above data indicate a dual role of AR in transcriptional regulation. Although the current androgen ablation therapy can repress the expression of growth-promoting genes that are activated by the AR, it may also attenuate the repressive role of AR on c-Met expression. Therefore, the therapeutic strategies to inhibit the activation of the HGF/c-Met pathway may be of benefit when combined with current androgen ablation treatment. [Cancer Res 2007;67(3):967–75]