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Dig Dis Sci. 2013 Mar;58(3):734-43. doi: 10.1007/s10620-012-2382-2. Epub 2012 Sep 25.

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

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  • 1Department of General Surgery, Qilu Hospital of Shandong University, No. 107 Wenhuaxi Road, Jinan, 250012, Shandong, China.

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.

PMID:
23007731
[PubMed - indexed for MEDLINE]
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