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Characterization of Insulin-Like Growth Factor-Binding Protein-Related Proteins (IGFBP-rPs) 1, 2, and 3 in Human Prostate Epithelial Cells: Potential Roles for IGFBP-rP1 and 2 in Senescence of the Prostatic Epithelium¹

Department of Pediatrics (A.L.-B., C.K.B., G.R.D., V.H., Y.O., R.G.R.), Oregon Health Sciences University, Portland, Oregon 97201; and Geriatric Research Education and Clinical Center (S.R.P.), Veterans Affairs Health Care System Puget Sound, Seattle/Tacoma, Washington 98493

Address all correspondence and requests for reprints to: Ron G. Rosenfeld, M.D., Department of Pediatrics, School of Medicine, Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97201-3098. E-mail: rosenfer{at}ohsu.edu

Insulin-like growth factor (IGF)-binding protein (IGFBP)-related proteins (IGFBP-rPs) are newly described cysteine-rich proteins that share significant aminoterminal structural similarity with the conventional IGFBPs and are involved in a diversity of biological functions, including growth regulation. IGFBP-rP1 (MAC25/Angiomodulin/prostacyclin-stimulating factor) is a potential tumor-suppressor gene that is differentially expressed in meningiomas, mammary and prostatic cancers, compared with their malignant counterparts. We have previously shown that IGFBP-rP1 is preferentially produced by primary cultures of human prostate epithelial cells (HPECs) and by poorly tumorigenic P69SV40T cells, compared with the cancerous prostatic LNCaP, DU145, PC-3, and M12 cells. We now show that IGFBP-rP1 increases during senescence of HPEC.

IGFBP-rP2 (also known as connective tissue growth factor), a downstream effector of transforming growth factor (TGF)-ß and modulator of growth for both fibroblasts and endothelial cells, was detected in most of the normal and malignant prostatic epithelial cells tested, with a marked up-regulation of IGFBP-rP2 during senescence of HPEC. Moreover, IGFBP-rP2 noticeably increased in response to TGF-ß1 and all-trans retinoic acid (atRA) in HPEC and PC-3 cells, and it decreased in response to IGF-I in HPEC.

IGFBP-rP3 [nephroblastoma overexpressed (NOV)], the protein product of the NOV protooncogene, was not detected in HPEC but was expressed in the tumorigenic DU145 and PC-3 cells. It was also synthesized by the SV40-T antigen-transformed P69 and malignant M12 cells, where it was down-regulated by atRA.

These observations suggest biological roles of IGFBP-rPs in the human prostate. IGFBP-rP1 and IGFBP-rP2 are likely to negatively regulate growth, because they seem to increase during senescence of the prostate epithelium and in response to growth inhibitors (TGF-ß1 and atRA). Although the data collected on IGFBP-rP3 in prostate are modest, its role as a growth stimulator and/or protooncogene is supported by its preferential expression in cancerous cells and its down-regulation by atRA.

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