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Endocrinology Vol. 140, No. 5 2372-2381
Copyright © 1999 by The Endocrine Society

ARTICLES

Androgen Receptor Up-Regulates Insulin-Like Growth Factor Binding Protein-5 (IGFBP-5) Expression in a Human Prostate Cancer Xenograft1

Christopher W. Gregory, Desok Kim, Ping Ye, A. Joseph D’Ercole, Thomas G. Pretlow, James L. Mohler and Frank S. French

The Laboratories for Reproductive Biology (C.W.G., F.S.F.), The Departments of Surgery (Division of Urology) (D.K., J.L.M.) and Pediatrics (C.W.G., F.S.F., P.Y., A.J.D.) and The Lineberger Comprehensive Cancer Center (A.J.D., J.L.M., F.S.F.), The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, Department of Pathology, Case Western Reserve University, Cleveland, Ohio (T.G.P.)

Address all correspondence and requests for reprints to: Frank S. French, The Laboratories for Reproductive Biology, Department of Pediatrics, CB 7500, 382 MSRB, Chapel Hill, North Carolina 27599. E-mail: fsfrench{at}med.unc.edu

The insulin-like growth factor (IGF) binding proteins (IGFBPs) are important modulators of IGF action in many tissues including human prostate. IGFBPs and the androgen receptor (AR) are expressed in CWR22, an androgen-dependent epithelial cell human CaP xenograft that retains biological characteristics of human CaPs, including regression following androgen withdrawal and recurrent growth of AR-containing cells in the absence of testicular androgens beginning several months after castration. Northern blot and in situ hybridization analyses demonstrated that IGFBP-5 is androgen-regulated in CWR22. IGFBP-5 messenger RNA (mRNA) decreased by 90% following castration of tumor-bearing mice compared with noncastrate androgen-stimulated mice. Testosterone treatment of CWR22 tumor-bearing mice 6 or 12 days after castration increased IGFBP-5 mRNA 10- to 12-fold. Levels of other IGFBP mRNAs did not change following androgen withdrawal and replacement. IGFBP-5 protein in tumor extracts bound 125I-labeled IGF-I in ligand blot assays and the amounts of IGFBP-5 measured by immunoblotting paralleled the levels of IGFBP-5 mRNA. Androgen-induced expression of IGFBP5 was at a maximum level within 24 h after testosterone replacement, whereas the major increase in cell proliferation as measured by Ki-67 immunostaining occurred between 24–48 h. This time course suggested IGFBP-5 may be a mediator of androgen-induced growth of CWR22. In tumors that recurred several months following castration, IGFBP-5 mRNA and protein increased to levels that approached those in androgen-stimulated CWR22 tumors from noncastrate mice. IGFBP-5 immunohistochemical staining of prostate tissue specimens from patients was stronger in androgen-dependent and androgen-independent CaP than in areas of intraepithelial neoplasia (PIN) or benign prostatic hyperplasia (BPH). IGFBP-5 mRNA in these specimens was localized predominantly to stromal cells and IGFBP-5 protein to epithelial cell membranes.




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