Qadan L R, Perez-Stable C M, Schwall R H, Burnstein K L, Ostenson R C, Howard G A, Roos B A
Geriatric Research, Education, and Clinical Center and Research Service, Veterans Affairs Medical Center, Department of Medicine, University of Miami School of Medicine, Florida 33101, USA.
Endocrinology. 2000 Jul;141(7):2567-73. doi: 10.1210/endo.141.7.7546.
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.
肝细胞生长因子（HGF）的受体MET的表达与雄激素不敏感型前列腺癌有关。在本研究中，我们评估了HGF对MET的激活作用以及HGF在前列腺癌细胞系中的作用。HGF可使三种雄激素无反应细胞系（DU 145、PC-3和ALVA-31）中的MET受体发生磷酸化（激活），并伴有形态学改变。尽管已知HGF能刺激包括前列腺正常上皮细胞在内的正常上皮细胞生长，但我们发现HGF可抑制ALVA-31和DU 145（激素难治性）细胞系的生长。此外，HGF和维生素D对每种雄激素无反应细胞系的生长具有累加抑制作用，其中对ALVA-31细胞的生长抑制作用最强。对ALVA-31细胞的进一步研究揭示了HGF和维生素D的独特协同作用。与维生素D抑制雄激素反应性细胞（LNCaP）时出现的G1期细胞积累不同，HGF和维生素D联合使用对雄激素无反应的ALVA-31细胞系的生长抑制作用降低了而非增加了G1期细胞的比例，同时使细胞周期后期阶段相应增加。这种细胞周期重新分布表明，在雄激素无反应的前列腺癌细胞中，HGF和维生素D共同作用，通过控制G1/S检查点以外的位点来减缓细胞周期进程，而G1/S检查点是雄激素敏感前列腺细胞生长控制的主要调节位点。
