title: The androgen receptor negatively regulates the expression of c-Met: implications for a novel mechanism of prostate cancer progression.
abstract: 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.
authors.affiliation: Departments of Urology and Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Meletios
authors.initials: M
authors.lastname: Verras
authors.forename: Jane
authors.initials: J
authors.lastname: Lee
authors.forename: Hui
authors.initials: H
authors.lastname: Xue
authors.forename: Tzu-Huey
authors.initials: TH
authors.lastname: Li
authors.forename: Yuzhuo
authors.initials: Y
authors.lastname: Wang
authors.forename: Zijie
authors.initials: Z
authors.lastname: Sun
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D018450:Disease Progression; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D011944:Receptors, Androgen / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000378:metabolism; D014162:Transfection; D014183:Transplantation, Heterologous
chemical_list: D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D016329:Sp1 Transcription Factor; D019859:Proto-Oncogene Proteins c-met