title: GABA-B receptor activation inhibits the in vitro migration of malignant hepatocytes.
abstract: There are conflicting data regarding whether activation of γ-aminobutyric acid-B (GABA-B) receptors results in inhibition of tumor growth and invasion. The objectives of this study were to document the effects of the GABA-B receptor agonist baclofen on malignant hepatocyte proliferation and migration. We also sought to determine whether any effects on cell migration were mediated by changes in cyclic adenosine monophosphate (cAMP) signaling or matrix metalloproteinase (MMP) expression. Finally, GABA-B(1) and -B(2) receptor expression was documented in 2 malignant hepatocyte cell lines (PLC/PRF/5 and Huh-7) and 12 sets of human hepatocellular carcinoma and adjacent nontumor tissues. Cell proliferative activity was documented by WST-1 absorbance, migration by wound healing assays, cAMP levels by enzyme-linked immunoassay (ELISA), MMP by immunohistochemistry and ELISA, and GABA-B receptor expression by flow cytometry and reverse transcriptase - polymerase chain reaction. Although baclofen had no effect on cell proliferation, wound healing was delayed, an effect that was reversed by the GABA-B receptor antagonist CGP. cAMP levels were decreased in Huh-7 but not PLC cells exposed to baclofen. MMP expression remained unaltered in both cell lines. Finally, GABA-B(1) receptor expression was present and consistently expressed, but GABA-B(2) expression was limited and varied with the number of cell passages and (or) duration of culture. In conclusion, activation of GABA-B receptors has no effect on malignant hepatocyte proliferation but does decrease cell migration. This inhibitory effect may involve cAMP signaling but not MMP expression. GABA-B(2) receptor expression is limited and variable, which may help to explain discrepancies with previously published results.
authors.affiliation: Section of Hepatology, Department of Medicine, University of Manitoba, Winnipeg, MB, Canada.
authors.forename: Carly
authors.initials: C
authors.lastname: Lodewyks
authors.forename: Jose
authors.initials: J
authors.lastname: Rodriguez
authors.forename: Jing
authors.initials: J
authors.lastname: Yan
authors.forename: Betty
authors.initials: B
authors.lastname: Lerner
authors.forename: Jeremy
authors.initials: J
authors.lastname: Lipschitz
authors.forename: Charles
authors.initials: C
authors.lastname: Nfon
authors.forename: Julia Darlene
authors.initials: JD
authors.lastname: Rempel
authors.forename: Julia
authors.initials: J
authors.lastname: Uhanova
authors.forename: Gerald Yosel
authors.initials: GY
authors.lastname: Minuk
mesh_terms: D001418:Baclofen / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects*; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D058786:GABA-B Receptor Agonists / Q000494:pharmacology*; D058788:GABA-B Receptor Antagonists / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D018080:Receptors, GABA-B / Q000378:metabolism*; D014945:Wound Healing / Q000187:drug effects
chemical_list: D058786:GABA-B Receptor Agonists; D058788:GABA-B Receptor Antagonists; D018080:Receptors, GABA-B; D000242:Cyclic AMP; D020782:Matrix Metalloproteinases; D001418:Baclofen