Role of stimulatory guanine nucleotide binding protein (G(s alpha)) in proliferation of PC-3M prostate cancer cells

Previous studies have shown that calcitonin-like immunoreactive substances are secreted by primary prostate cells. Furthermore, exogenously added calc itonin stimulates proliferation of androgen-responsive LnCaP cells. To exam ine the possible effect of calcitonin on growth of invasive prostate cancer cells, we tested its effects on proliferation of PC-3M cells. Calcitonin s timulated DNA synthesis of PC-3M cells in a dose-dependent fashion, and als o stimulated adenylyl cyclase and protein kinase C activities, To further d elineate the role of these signaling cascades in proliferation of PC-3M pro state cancer cells, we selectively activated these pathways by transfecting cDNAs expressing constitutively active forms of either G(s)alpha (G(s)alph a -QL) or G(q)alpha (G(q)alpha -QL). cDNAs expressing wild type forms of G- proteins (G(s)alpha -WT and G(q)alpha -WT) were used as vehicle controls. G (q)alpha -QL transfectants exhibited growth inhibition and terminal differe ntiation. Those expressing G(s)alpha -QL exhibited a dramatic increase in g rowth rate. G(s)alpha -QL transfectants displayed an almost 3-fold increase in [H-3]-thymidine incorporation and over a 4-fold increase in growth rate when compared with parental PC-3M cells or those expressing wild-type G(s) alpha (G(s)alpha -WT). The growth-promoting action of G(s)alpha -QL could n ot be mimicked by either 8-bromo cAMP or forskolin, However, nifedipine, a calcium channel antagonist, potently and selectively inhibited DNA synthesi s in G(s)alpha -QL transfectants, These results suggest that the growth-pro moting actions of G(s)alpha On PC-3M cells may be mediated by nifedipine-se nsitive proliferative events, (C) 2001 Wiley-Liss, Inc.