gamma-Aminobutyric acid inhibits cholangiocarcinoma growth by cyclic AMP-dependent regulation of the protein kinase A/extracellular signal-regulated kinase 1/2 pathway.

Abstract

We studied the effect of the inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), in the regulation of cholangiocarcinoma growth. We determined the in vitro effect of GABA on the proliferation of the cholangiocarcinoma cell lines (Mz-ChA-1, HuH-28, and TFK-1) and evaluated the intracellular pathways involved. The effect of GABA on migration of Mz-ChA-1 cells was also evaluated. In vivo, Mz-ChA-1 cells were s.c. injected in athymic mice, and the effects of GABA on tumor size, tumor cell proliferation, apoptosis, collagen quantity, and the expression of vascular endothelial growth factor-A (VEGF-A) and VEGF-C (cancer growth regulators) were measured after 82 days. GABA decreased in vitro cholangiocarcinoma growth in a time-dependent and dose-dependent manner, by both cyclic AMP/protein kinase A- and D-myo-inositol-1,4,5-thriphosphate/Ca(2+)-dependent pathways, leading to down-regulation of extracellular signal-regulated kinase 1/2 phosphorylation. Blocking of GABA(A), GABA(B), and GABA(C) receptors prevented GABA inhibition of cholangiocarcinoma proliferation. GABA inhibited Mz-ChA-1 cell migration and, in vivo, significantly decreased tumor volume, tumor cell proliferation, and VEGF-A/C expression whereas increasing apoptosis compared with controls. An increase in collagen was evident in GABA-treated tumors. GABA decreases biliary cancer proliferation and reduces the metastatic potential of cholangiocarcinoma. GABA may represent a therapeutic agent for patients affected by malignancies of the biliary tract.

• Authors: Giammarco Fava, Luca Marucci, Shannon Glaser, Heather Francis, Sharon De Morrow, Antonio Benedetti, Domenico Alvaro, Julie Venter, Cynthia Meininger, Tushar Patel, Silvia Taffetani, Marco Marzioni, Ryun Summers, Ramona Reichenbach, Gianfranco Alpini
• Journal: Cancer research (Cancer Res) Vol. 65 Issue 24 Pg. 11437-46 (Dec 15 2005) ISSN: 0008-5472 [Print] United States
• PMID: 16357152 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• GABA Agents
• Receptors, GABA-A
• Receptors, GABA-B
• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factor C
• gamma-Aminobutyric Acid
• Collagen
• Cyclic AMP
• Cyclic AMP-Dependent Protein Kinases
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3

Topics

• Animals
• Bile Duct Neoplasms (drug therapy, enzymology, pathology)
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Cholangiocarcinoma (drug therapy, enzymology, pathology)
• Collagen (metabolism)
• Cyclic AMP (pharmacology)
• Cyclic AMP-Dependent Protein Kinases (metabolism)
• GABA Agents (therapeutic use)
• Humans
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Phosphorylation
• Receptors, GABA-A (metabolism)
• Receptors, GABA-B (metabolism)
• Signal Transduction
• Tumor Cells, Cultured
• Vascular Endothelial Growth Factor A (metabolism)
• Vascular Endothelial Growth Factor C (metabolism)
• gamma-Aminobutyric Acid (therapeutic use)