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Restoration of Insulin-Like Growth Factor Binding Protein-Related Protein 1 Has a Tumor-Suppressive Activity through Induction of Apoptosis in Human Prostate Cancer

¹ Department of Urology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan;
² Department of Urology, Shimane Medical University, Izumo, Japan;
³ Urology Research Center, Department of Urology, University of California San Francisco and Veterans Affairs Medical Center, San Francisco, California

Insulin-like growth factor binding protein-related protein 1 (IGFBP-rP1), a member of the IGFBP super family, is down-regulated at the mRNA level in several solid cancers. We hypothesize that IGFBP-rP1 has a tumor-suppressive effect on prostate cancer growth and its inactivation is through CpG hypermethylation. We tested this hypothesis through expression analysis of IGFBP-rP1, transfection studies, growth analysis, and CpG methylation in prostate cancer cells and tissues. In situ hybridization revealed IGFBP-rP1 mRNA expression was detected in the stroma and epithelium of benign prostatic hyperplasia tissues but was either weak or lost in prostate cancer tissues. The mRNA expression for IGFBP-rP1 was lacking in DU145, LNCaP, ND-1, and PC-3 prostate cancer cell lines, and after demethylation (5-aza-dC treatment), the expression was restored suggesting that methylation inactivated IGFBP-rP1 expression in prostate cancer cells. We further tested whether transfection of IGFBP-rP1 can modulate prostate cancer cells growth. We transfected PC-3 cell lines with IGFBP-rP1 cDNA (PC-3-rP1) and Northern blotting confirmed mRNA transcript of IGFBP-rP1 in these PC-3-rP1 clones. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay showed growth rate was significantly lower in PC-3-rP1 cells than in the nontransfected control. In addition, the medium obtained from PC-3-rP1 cells reduced the growth rate in both PC-3-rP1 and control PC-3 cells. A soft agar colony-forming assay revealed that colony formation was markedly decreased in PC-3-rP1 cells. The number of apoptotic cells and caspase-3 expression were increased in the PC-3-rP1 cells as compared with control PC-3 cells. This is the first study that suggests inactivation of IGFBP-rP1 is through CpG methylation, and tumor-suppressive activity of IGFBP-rP1 is through induction of apoptosis in an IGF-I independent manner in prostate cancer.

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