This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend 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 HighWire Citing Articles via Google Scholar Google Scholar Articles by Mutaguchi, K. Articles by Usui, T. Search for Related Content PubMed PubMed Citation Articles by Mutaguchi, K. Articles by Usui, T.

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.

This article has been cited by other articles:

				W. M. Gommans, N. E. Tatalias, C. P. Sie, D. Dupuis, N. Vendetti, L. Smith, R. Kaushal, and S. Maas Screening of human SNP database identifies recoding sites of A-to-I RNA editing RNA, October 1, 2008; 14(10): 2074 - 2085. [Abstract] [Full Text] [PDF]

				I. Osman, D. F. Bajorin, T.-T. Sun, H. Zhong, D. Douglas, J. Scattergood, R. Zheng, M. Han, K. W. Marshall, and C.-C. Liew Novel blood biomarkers of human urinary bladder cancer. Clin. Cancer Res., June 1, 2006; 12(11): 3374 - 3380. [Abstract] [Full Text] [PDF]

				A. Wallqvist, J. Connelly, E. A. Sausville, D. G. Covell, and A. Monks Differential Gene Expression as a Potential Classifier of 2-(4-Amino-3-methylphenyl)-5-fluorobenzothiazole-Sensitive and -Insensitive Cell Lines Mol. Pharmacol., March 1, 2006; 69(3): 737 - 748. [Abstract] [Full Text] [PDF]

				M. Gronborg, T. Z. Kristiansen, A. Iwahori, R. Chang, R. Reddy, N. Sato, H. Molina, O. N. Jensen, R. H. Hruban, M. G. Goggins, et al. Biomarker Discovery from Pancreatic Cancer Secretome Using a Differential Proteomic Approach Mol. Cell. Proteomics, January 1, 2006; 5(1): 157 - 171. [Abstract] [Full Text] [PDF]

				W. Chu, Z. Ghahramani, F. Falciani, and D. L. Wild Biomarker discovery in microarray gene expression data with Gaussian processes Bioinformatics, August 15, 2005; 21(16): 3385 - 3393. [Abstract] [Full Text] [PDF]

				M. F. McCarty Targeting Multiple Signaling Pathways as a Strategy for Managing Prostate Cancer: Multifocal Signal Modulation Therapy Integr Cancer Ther, December 1, 2004; 3(4): 349 - 380. [Abstract] [PDF]