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Effect of a Vitamin D₃ Analogue on Keratinocyte Growth Factor-Induced Cell Proliferation in Benign Prostate Hyperplasia¹

Department of Clinical Physiopathology, Endocrinology Unit (C.C., R.S., M.S.) and Andrology Unit (M.M., M.L., G.F.); Department of Anatomy Histology and Forensic Medicine (G.B.V., M.G.), University of Florence, Florence; and Department of Clinical and Experimental Medicine (T.B.), University of Catanzaro, Catanzaro, Italy

Address correspondence and requests for reprints to: Mario Maggi, Department of Clinical Physiopathology, Andrology Unit, University of Florence, Viale Pieraccini, 6, 50139-Florence, Italy. E-mail: m.maggi{at}dfc.unifi.it

Prostate enlargement and function is under the dual control of androgens and intraprostatic growth factors. They regulate, in concert, prostate cell proliferation and apoptosis. An increased signaling of both growth factors and androgens are supposed to underlie benign prostate hyperplasia (BPH), one of the more common disorders of the aging male. Since, in clinical practice, androgen ablation resulted in a rather limited decrease in prostate volume, therapeutic strategies targeting intraprostatic growth factors are emerging. The activated form of vitamin D, vitamin D₃, and some of its analogues have been described as potent regulators of cell growth and differentiation. In this study, we report the effects of one of these vitamin D₃ analogues, 1,25-dihydroxy-16ene-23yne D₃, or analogue (V), on the fate of isolated epithelial cells derived from patients with BPH. We essentially found that analogue (V), as well as vitamin D_3, inhibited BPH cell proliferation and counteracted the mitogenic activity of a potent growth factor for BPH cells, such as keratinocyte growth factor (KGF). Moreover, analogue (V) induced bcl-2 protein expression, intracellular calcium mobilization, and apoptosis in both unstimulated and KGF-stimulated BPH cells. Since a short-term (5-min) incubation with analogue (V) reduced the KGF-induced tyrosine phosphorylation of a 120-kDA protein, corresponding to the KGF receptor, a rapid and direct cross-talk between these two molecules is suggested. Such a rapid effect of analogue (V), together with the transient induction of intracellular calcium waves, seems to indicate the partial involvement of a membrane, nongenomic receptor for vitamin D₃. In conclusion, we demonstrated the antiproliferative and proapoptotic effect of analogue (V) in BPH cells and speculated on its possible use in the therapy of BPH.

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