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

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

Research output: Contribution to journalArticlepeer-review

71 Scopus citations

Abstract

We studied the effect of the inhibitory neurotransmitter, γ-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.

Original languageEnglish (US)
Pages (from-to)11437-11446
Number of pages10
JournalCancer research
Volume65
Issue number24
DOIs
StatePublished - Dec 15 2005

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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