Abstract
M.J. Cantoria , L.G. Boros , E.J. Meuillet . Dept. of Nutritional Sciences, The University of Arizona, Tucson, AZ, USA 2 SiDMAP, LLC, Los Angeles, CA, USA Harbor-UCLA Research and Education Institute, UCLA School of Medicine, Torrance, CA, USA Arizona Cancer Center, Tucson, AZ, USA Pancreatic adenocarcinoma is an aggressive malignancy that is very difficult to diagnose and treat. Systemic treatment of pancreatic cancer, either with a single agent or a combination of agents, has shown only modest benefits. Epidemiological studies have reported a lower incidence of pancreatic cancer in diabetics treated with the biguanide metformin but the mechanism bywhich it exerts its putative anti-cancer effects has yet to be elucidated. Using 1,2-13C glucose labeling we show for the first time that metformin (100mM) exerts metabolic control on the pancreatic cancer cell lines BxPC-3 (WT KRAS) and MIAPaCa-2 (G12C-KRAS). Compared to control MIAPaCa-2 cells, metformin inhibits tricarboxylic acid (TCA) cycle turnover in cells grown in media supplemented with 1mM cholesteryl hemisuccinate (CHS), as indicated by decreased CO2 production in the MIAPaCa-2-CHS-metformin group (8.70+0.82 vs 5.31+0.82, p1⁄40.01). Compared to their cell line-specific controls, metformin increases extracellular lactate labeling in CHS-BxPC-3 (8.79+0.78 vs 11.11+0.45, p1⁄40.02) and CHS-MIAPaCa-2 (10.75+0.65 vs 17.79+1.31 vs, p1⁄40.004) cells, providing evidence that metformin prevents pyruvate from entering the TCA cycle. Metformin also inhibits succinate formation and the activities of pyruvate dehydrogenase and pyruvate carboxylase as measured by glutamate labeling. Metformin decreases new fatty acid synthesis in CHStreated BxPC-3 (3.86+0.42 vs 8.17+0.78, p1⁄40.002) and MIAPaCa-2 (11.30+0.81 vs 15.30+0.96, p1⁄40.006) compared to the groups that were not metformin-treated. Understanding the mechanism behind the phenotypic differences in metformin's control of metabolic fluxes in these two cell lines will help support the application of metformin as a potential anticancer drug and potentially discover novel drug targets for pancreatic cancer.
Published Version
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
