H3 Histamine Receptor–Mediated Activation of Protein Kinase Cα Inhibits the Growth of Cholangiocarcinoma In vitro and In vivo
| Autor: | Sharon DeMorrow, Paolo Onori, Heather Francis, Julie Venter, Eugenio Gaudio, Gianfranco Alpini, Roberta Sferra, Antonio Franchitto, Fanyin Meng, Romina Mancinelli, Shelley Kopriva, Mellanie White, Antonella Vetuschi, Guido Carpino |
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| Rok vydání: | 2009 |
| Předmět: |
Male
Vascular Endothelial Growth Factor A MAPK/ERK pathway Cancer Research medicine.medical_specialty Protein Kinase C-alpha Antineoplastic Agents Biology liver Article Cholangiocarcinoma Histamine Agonists Mice biliary tree histamine Cell Line Tumor Internal medicine medicine Animals Humans Receptors Histamine H3 Histidine Phosphorylation Protein kinase A Molecular Biology Protein kinase C Mice Inbred BALB C Mitogen-Activated Protein Kinase 3 Cell growth Kinase Methylhistamines Molecular biology Enzyme Activation Disease Models Animal Vascular endothelial growth factor A Bile Ducts Intrahepatic Receptors Vascular Endothelial Growth Factor Treatment Outcome Endocrinology Bile Duct Neoplasms Oncology Cancer research Signal transduction Signal Transduction |
| Zdroj: | Molecular Cancer Research. 7:1704-1713 |
| ISSN: | 1557-3125 1541-7786 |
| DOI: | 10.1158/1541-7786.mcr-09-0261 |
| Popis: | 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) |
| Databáze: | OpenAIRE |
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