title: 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.affiliation: Central Texas Veterans Health Care System, Research Service, College of Medicine, Temple, 76504, USA. galpini@tamu.edu
authors.forename: Giammarco
authors.initials: G
authors.lastname: Fava
authors.forename: Luca
authors.initials: L
authors.lastname: Marucci
authors.forename: Shannon
authors.initials: S
authors.lastname: Glaser
authors.forename: Heather
authors.initials: H
authors.lastname: Francis
authors.forename: Sharon
authors.initials: S
authors.lastname: De Morrow
authors.forename: Antonio
authors.initials: A
authors.lastname: Benedetti
authors.forename: Domenico
authors.initials: D
authors.lastname: Alvaro
authors.forename: Julie
authors.initials: J
authors.lastname: Venter
authors.forename: Cynthia
authors.initials: C
authors.lastname: Meininger
authors.forename: Tushar
authors.initials: T
authors.lastname: Patel
authors.forename: Silvia
authors.initials: S
authors.lastname: Taffetani
authors.forename: Marco
authors.initials: M
authors.lastname: Marzioni
authors.forename: Ryun
authors.initials: R
authors.lastname: Summers
authors.forename: Ramona
authors.initials: R
authors.lastname: Reichenbach
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Alpini
mesh_terms: D000818:Animals; D001650:Bile Duct Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018281:Cholangiocarcinoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D003094:Collagen / Q000378:metabolism; D000242:Cyclic AMP / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D018682:GABA Agents / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010766:Phosphorylation; D011963:Receptors, GABA-A / Q000378:metabolism; D018080:Receptors, GABA-B / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000627:therapeutic use*
chemical_list: D018682:GABA Agents; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; D005680:gamma-Aminobutyric Acid; D003094:Collagen; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3