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

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 D-3, 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 D, analogues, 1,25-dihydroxy-16ene-23yne D-3, 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 D-3. 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.