H3 Histamine Receptor–Mediated Activation of Protein Kinase Cα Inhibits the Growth of Cholangiocarcinoma In vitro and In vivo
Open Access
- 23 October 2009
- journal article
- Published by American Association for Cancer Research (AACR) in Molecular Cancer Research
- Vol. 7 (10), 1704-1713
- https://doi.org/10.1158/1541-7786.mcr-09-0261
Abstract
Histamine regulates functions via four receptors (HRH1, HRH2, HRH3, and HRH4). The d-myo-inositol 1,4,5-trisphosphate (IP3)/Ca2+/protein kinase C (PKC)/mitogen-activated protein kinase pathway regulates cholangiocarcinoma growth. We evaluated the role of HRH3 in the regulation of cholangiocarcinoma growth. Expression of HRH3 in intrahepatic and extrahepatic cell lines, normal cholangiocytes, and human tissue arrays was measured. In Mz-ChA-1 cells stimulated with (R)-(α)-(−)-methylhistamine dihydrobromide (RAMH), we measured (a) cell growth, (b) IP3 and cyclic AMP levels, and (c) phosphorylation of PKC and mitogen-activated protein kinase isoforms. Localization of PKCα was visualized by immunofluorescence in cell smears and immunoblotting for PKCα in cytosol and membrane fractions. Following knockdown of PKCα, Mz-ChA-1 cells were stimulated with RAMH before evaluating cell growth and extracellular signal–regulated kinase (ERK)-1/2 phosphorylation. In vivo experiments were done in BALB/c nude mice. Mice were treated with saline or RAMH for 44 days and tumor volume was measured. Tumors were excised and evaluated for proliferation, apoptosis, and expression of PKCα, vascular endothelial growth factor (VEGF)-A, VEGF-C, VEGF receptor 2, and VEGF receptor 3. HRH3 expression was found in all cells. RAMH inhibited the growth of cholangiocarcinoma cells. RAMH increased IP3 levels and PKCα phosphorylation and decreased ERK1/2 phosphorylation. RAMH induced a shift in the localization of PKCα expression from the cytosolic domain into the membrane region of Mz-ChA-1 cells. Silencing of PKCα prevented RAMH inhibition of Mz-ChA-1 cell growth and ablated RAMH effects on ERK1/2 phosphorylation. In vivo, RAMH decreased tumor growth and expression of VEGF and its receptors; PKCα expression was increased. RAMH inhibits cholangiocarcinoma growth by PKCα-dependent ERK1/2 dephosphorylation. Modulation of PKCα by histamine receptors may be important in regulating cholangiocarcinoma growth. (Mol Cancer Res 2009;7(10):1704–13)Keywords
This publication has 50 references indexed in Scilit:
- Antitumoral Activity of Rapamycin Mediated Through Inhibition of HIF-1alpha and VEGF in Hepatocellular CarcinomaDigestive Diseases and Sciences, 2008
- Multifunctional effect of epigallocatechin-3-gallate (EGCG) in downregulation of gelatinase-A (MMP-2) in human breast cancer cell line MCF-7Life Sciences, 2008
- Serotonin Metabolism Is Dysregulated in Cholangiocarcinoma, which Has Implications for Tumor GrowthCancer Research, 2008
- Small mouse cholangiocytes proliferate in response to H1 histamine receptor stimulation by activation of the IP3/CaMK I/CREB pathwayAmerican Journal of Physiology-Cell Physiology, 2008
- Epidemiology, risk factors, and pathogenesis of cholangiocarcinomaHPB, 2008
- The RBCC GeneRFP2(Leu5) Encodes a Novel Transmembrane E3 Ubiquitin Ligase Involved in ERADMolecular Biology of the Cell, 2007
- Histamine H3-receptor signaling in cardiac sympathetic nerves: Identification of a novel MAPK-PLA2-COX-PGE2-EP3R pathwayBiochemical Pharmacology, 2007
- COX-2-mediated stimulation of the lymphangiogenic factor VEGF-C in human breast cancerBritish Journal of Cancer, 2006
- Activation of protein kinase C alpha is required for TPA-triggered ERK (MAPK) signaling and growth inhibition of human hepatoma cell HepG2Journal of Biomedical Science, 2005
- Biliary adenocarcinomaJournal of Hepatology, 1985