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Cell and Tumor Biology |
-Aminobutyric Acid Inhibits Cholangiocarcinoma Growth by Cyclic AMP–Dependent Regulation of the Protein Kinase A/Extracellular Signal-Regulated Kinase 1/2 Pathway
1 Central Texas Veterans Health Care System, Research Service; Departments of 2 Medicine and 3 Medical Physiology; 4 Division R&E, Scott & White Hospital and The Texas A&M University System Health Science Center, College of Medicine, Temple, Texas; 5 Department of Gastroenterology, Polytechnic University of Marche, Ancona, Italy; and 6 Division of Gastroenterology, La Sapienza University, Rome, Italy
Requests for reprints: Gianfranco Alpini, The Texas A&M University System Health Science Center, College of Medicine, Medical Research Building, 702 Southwest H.K. Dodgen Loop, Temple, TX 76504. Phone: 254-742-7044; Fax: 254-724-5944; E-mail: galpini{at}tamu.edu.
We studied the effect of the inhibitory neurotransmitter, 
-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/Ca2+-dependent pathways, leading to down-regulation of extracellular signal-regulated kinase 1/2 phosphorylation. Blocking of GABAA, GABAB, and GABAC 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. (Cancer Res 2005; 65(24): 11437-46)
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