The Effect And Mechanism Of Metformin On The Cholangiocarcinoma Cell Lines Mz-ChA-1 And QBC939

Cholangiocarcinoma(CCA),a hepatobiliary malignancy originating from varying locations within bile ducts,is the second most frequent hepatic malignancy after hepatocellular carcinoma(HCC).Surgical intervention offers the highest chance to cure for all types of cholangiocarcinoma.Unfortunately,individuals presenting with CCA are usually asymptomatic;at the time of diagnosis,most of patients no longer can benefit from surgical resection.Systemic chemotherapy and targeted radiation therapy are also applied for the treatment of CCAs.Nevertheless,these approaches are failed to significantly improve the prognosis of CCA.In this case,new therapy strategies are urgently needed for CCA.Metformin is a widely prescribed anti-diabetes drug of the biguanide family,which has a potential utility for cancer therapy due to recent epidemiological research and clinical trials.In the present study,we observed that metformin inhibits the proliferation of CCA cell lines Mz-ChA-1 and QB939 in a dose-dependent manner.While metformin is considered to associate with multiple pathways in cells,how do exactly these perturbed pathways cross interact and finally transduce to its anticancer properties is remain unclear.Metabolomic analysis offers a unique insight into clarifying the mechanism of metformin.As metabolites are the final downstream products of gene transcription and translation,variations in metabolite levels reflect the systemic change of biological states.Using NMR-based metabolomic analysis,we showed a distinct separation in metabolic profiles between metformin treated or non-treated CCAs.For further investigation,metabolites were identified based on the spectra and followed by derived correlation analysis and pathway analysis.Our data indicate that metformin mainly disturbs the metabolism of CCA cells in following aspects:(1)metformin increases the fluxes of glucose to lactate by boosting glycolysis and inhibiting TCA cycle;(2)metformin accelerates the consumption of TCA-adjacent amino acids and impairs the biosynthesis of other non-essential amino acids;(3)metformin restrains the catabolism of branch-chained amino acids.These findings may provide valuable information to evaluate the clinical usability of metformin on CCA management.