Gamma-aminobutyric acid binds to GABAb receptor to inhibit cholangiocarcinoma cells growth via the JAK/STAT3 pathway.

Abstract

BACKGROUND:

Gamma-aminobutyric acid (GABA) has been reported to inhibit the growth of cholangiocarcinoma QBC939 cells, but the mechanisms are still not fully understood.

AIMS:

To explore the mechanisms of the anti-cancer effect of GABA on QBC939 cells.

METHODS:

An initial immunohistochemistry study of the expressions of GABA receptors in cholangiocarcinoma tissues was followed by the culture and treatment of QBC939 cells for 48 h with GABA, GABA + bicuculine (GABAA receptor antagonist), GABA + phaclofen (GABAB receptor antagonist), and GABA + AG490 (Janus Kinase inhibitor). MTT and Annexin V-FITC/PI binding assays were used to determine the proliferation and apoptosis of the QBC939 cells. The expression of the signal transducer and activator of transcription 3 (STAT3) and phosphorylated STAT3 (Tyr705) [p-STAT3 (Tyr705)] was evaluated by the western blot assay. The effect of GABA on the growth of QBC939 xenograft tumors in athymic nu/nu mice was examined, and p-STAT3 (Tyr705) expression in xenograft tumors was detected by immunohistochemistry.

RESULTS:

A significant difference was only observed in GABAB receptor expression between cholangiocarcinoma and normal bile tissues. The MTT and Annexin V-FITC/PI assays showed that the antiproliferative and proapoptotic effects of GABA on QBC939 cells could be antagonized by phaclofen and AG490, but not bicuculine. GABA significantly down-regulated p-STAT3 (Tyr705) expression; this action was also antagonized by phaclofen and AG490. GABA also effectively inhibited xenograft tumor growth, and p-STAT3 (Tyr705) expression was significantly decreased in GABA-treated xenograft tumors.

CONCLUSIONS:

GABA may inhibit the growth of cholangiocarcinoma QBC939 cells through the GABAB receptor, and the anti-cancer effects may be partly mediated via the JAK/STAT3 pathway.

• Authors: Qiang Huang, Cheng-Lin Zhu, Chen-Hai Liu, Fang Xie, Kai Zhu, San-Yuan Hu
• Journal: Digestive diseases and sciences (Dig Dis Sci) Vol. 58 Issue 3 Pg. 734-43 (Mar 2013) ISSN: 1573-2568 [Electronic] United States
• PMID: 23007731 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, GABA-B
• STAT3 Transcription Factor
• gamma-Aminobutyric Acid
• Janus Kinases

Topics

• Animals
• Cell Line, Tumor
• Cholangiocarcinoma (metabolism, pathology)
• Gene Expression Regulation, Neoplastic
• Humans
• Janus Kinases (genetics, metabolism)
• Mice
• Mice, Nude
• Neoplasms, Experimental (metabolism)
• Protein Binding
• Receptors, GABA-B (genetics, metabolism)
• STAT3 Transcription Factor (genetics, metabolism)
• gamma-Aminobutyric Acid (metabolism)