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

J Hepatol. 2001 Feb;34(2):284-91. doi: 10.1016/s0168-8278(00)00025-8.

Abstract

Background/aims: We determined the role of gastrin in the regulation of cholangiocarcinoma 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, HuH-28 and TFK-1 cells. We evaluated the effect of gastrin on growth and apoptosis of Mz-ChA-1 in the absence or presence of inhibitors for CCK-A (L-364, 718) and CCK-B/gastrin (L-365, 260) receptors, the intracellular Ca2+ chelator (BAPTA/AM), and the protein kinase C (PKC)-alpha inhibitor, H7. We evaluated 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 cells in a dose- and time-dependent fashion. The antiproliferative effect of gastrin on Mz-ChA-1 cells was inhibited by L-365, 260, H7 and BAPTA/AM but not L-364, 718. Gastrin induced membrane translocation of PKC-alpha. The inhibition 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 cells. Gastrin inhibits growth and induces apoptosis in Mz-ChA-1 cells through the Ca2+-dependent PKC-alpha. The data suggest a therapeutic role for gastrin in the modulation of cholangiocarcinoma growth.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / pharmacology
  • Apoptosis / drug effects*
  • Benzodiazepinones / pharmacology
  • Cell Division / drug effects
  • Cholangiocarcinoma / drug therapy*
  • Cholangiocarcinoma / metabolism
  • Cholangiocarcinoma / pathology*
  • Egtazic Acid / analogs & derivatives
  • Egtazic Acid / pharmacology
  • Enzyme Activation / drug effects
  • Gastrins / pharmacology*
  • Humans
  • Isoenzymes / metabolism*
  • Phenylurea Compounds / pharmacology
  • Protein Kinase C / metabolism*
  • Protein Kinase C-alpha
  • Receptor, Cholecystokinin A
  • Receptor, Cholecystokinin B
  • Receptors, Cholecystokinin / antagonists & inhibitors
  • Receptors, Cholecystokinin / metabolism
  • Tumor Cells, Cultured

Substances

  • Benzodiazepinones
  • Gastrins
  • Isoenzymes
  • Phenylurea Compounds
  • Receptor, Cholecystokinin A
  • Receptor, Cholecystokinin B
  • Receptors, Cholecystokinin
  • 1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester
  • L 365260
  • Egtazic Acid
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
  • PRKCA protein, human
  • Protein Kinase C
  • Protein Kinase C-alpha