γ-aminobutyric acid B2 receptor: A potential therapeutic target for cholangiocarcinoma in patients with diabetes mellitus

Figure 6 Schematic summary of the effects of high glucose on γ-aminobutyric acid B2 receptor expression and the effects of baclofen on cholangiocarcinoma cells. High glucose induces the expression of γ-aminobutyric acid B2 receptor (GABBR2) in cholangiocarcinoma (CCA) cells. The treatment of baclofen, a GABBR2 agonist, to CCA cells inhibits phosphorylation of glycogen synthase kinase 3, resulting in the activation of the kinase activity which further phosphorylates β-catenin. Phosphorylated β-catenin is subjected to degradation preventing its function on promoting cell proliferation via c-Myc and cyclin D1 expression. On the other hand, activated GABBR2 by baclofen also inhibits phosphorylation of signal transducer and activator of transcription 3 (STAT3). The inhibition of STAT3 phosphorylation also suppresses its functions as a transcription factor for c-Myc and cyclin D1 expression. Activating GABBR2 by baclofen, thus, suppresses the proliferation of CCA cells. GABBR2: γ-aminobutyric acid B2 receptor; GSK3: Glycogen synthase kinase 3; STAT3: Signal transducer and activator of transcription 3.