Gastrin inhibits cholangiocarcinoma growth through increased apoptosis by activation of Ca2+-dependent protein kinase C-alpha

Background/Aims: We determined the role of gastrin in the regulation of cho langiocarcinoma growth. Methods: We evaluated for the functional presence of cholecystokinin (CCK)- B/gastrin receptors in the cholangiocarcinoma cell lines, Mz-ChA-1, HuH-28 and TFK-1, We determined the effect of gastrin on the growth of Mz-ChA-1, H uH-28 and TFK-1 cells. We evaluated the effect of gastrin on growth and apo ptosis of Mz-ChA-1 in the absence or presence of inhibitors for CCK-A (L-36 4, 718) and CCK-B/gastrin (L-365, 260) receptors, the intracellular Ca2+ ch elator (BAPTA/AM), and the protein kinase C (PKC)-alpha inhibitor, H1. We e valuated if gastrin effects on Mz-ChA-1 growth and apoptosis are associated with membrane translocation of PKC-alpha. Results: Gastrin inhibited DNA synthesis of Mz-ChA-1, HuH-28 and TFK-1 cell s in a dose- and time-dependent fashion. The antiproliferative effect of ga strin on Mz-ChA-1 cells was inhibited by L-365, 260, H7 and BAPTA/AM but no t L-364, 718. Gastrin induced membrane translocation of PKC-alpha. The inhi bition of growth of Mz-ChA-1 cells by gastrin was associated with increased apoptosis through a PKC-dependent mechanism. Conclusions: Gastrin inhibits the growth of Mz-ChA-1, HuH-28 and TFK-1 cell s. Gastrin inhibits growth and induces apoptosis in Mz-ChA-1 cells through the Ca2+-dependent PKC-alpha. The data suggest a therapeutic role for gastr in in the modulation of cholangiocarcinoma growth. (C) 2001 European Associ ation for the Study of the Liver. Published by Elsevier Science B.V. All ri ghts reserved.