title: 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.
  
  
  OBJECTIVE
  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.affiliation: Department of General Surgery, Qilu Hospital of Shandong University, No. 107 Wenhuaxi Road, Jinan, 250012, Shandong, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Huang
authors.forename: Cheng-Lin
authors.initials: CL
authors.lastname: Zhu
authors.forename: Chen-Hai
authors.initials: CH
authors.lastname: Liu
authors.forename: Fang
authors.initials: F
authors.lastname: Xie
authors.forename: Kai
authors.initials: K
authors.lastname: Zhu
authors.forename: San-Yuan
authors.initials: SY
authors.lastname: Hu
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053612:Janus Kinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000378:metabolism; D011485:Protein Binding; D018080:Receptors, GABA-B / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D018080:Receptors, GABA-B; D050796:STAT3 Transcription Factor; D005680:gamma-Aminobutyric Acid; D053612:Janus Kinases