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Hepatocyte Growth Factor and Vitamin D Cooperatively Inhibit Androgen-Unresponsive Prostate Cancer Cell Lines¹

Geriatric Research, Education, and Clinical Center and Research Service, Veterans Affairs Medical Center (L.R.Q., C.M.P.-S., K.L.B., G.A.H., B.A.R.); and Departments of Medicine (L.R.Q., C.M.P.-S., G.A.H., B.A.R.), Molecular and Cellular Pharmacology (K.L.B.), Biochemistry and Molecular Biology (G.A.H.), and Neurology (B.A.R.), and Sylvester Comprehensive Cancer Center (L.R.Q., C.M.P.-S., K.L.B., G.A.H., B.A.R.), University of Miami School of Medicine, Miami, Florida 33101; Genentech, Inc. (R.H.S.), South San Francisco, California 94080; and Good Samaritan Cancercare and Research Center (R.C.O.), Puyallup, Washington 98371

Address all correspondence and requests for reprints to: Bernard A. Roos, M.D., University of Miami School of Medicine, P.O. Box 016960 (D-503), Miami, Florida 33101. E-mail: broos{at}med.miami.edu

Expression of MET, the receptor for hepatocyte growth factor (HGF), has been associated with androgen-insensitive prostate cancer. In this study we evaluated MET activation by HGF and HGF action in prostate cancer cell lines. HGF causes phosphorylation (activation) of the MET receptor in three androgen-unresponsive cell lines (DU 145, PC-3, and ALVA-31) together with morphological change. Although HGF is known to stimulate the growth of normal epithelial cells, including those from prostate, we found that HGF inhibited ALVA-31 and DU 145 (hormone-refractory) cell lines. Moreover, HGF and vitamin D additively inhibited growth in each androgen-unresponsive cell line, with the greatest growth inhibition in ALVA-31 cells. Further studies in ALVA-31 cells revealed distinct cooperative actions of HGF and vitamin D. In contrast to the accumulation of cells in G₁ seen during vitamin D inhibition of androgen-responsive cells (LNCaP), growth inhibition of the androgen-unresponsive ALVA-31 cell line with the HGF and vitamin D combination decreased, rather than increased, the fraction of cells in G₁, with a corresponding increase in the later cell cycle phases. This cell cycle redistribution suggests that in androgen-unresponsive prostate cancer cells, HGF and vitamin D act together to slow cell cycle progression via control at sites beyond the G₁/S checkpoint, the major regulatory locus of growth control in androgen-sensitive prostate cells.

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