Abstract 11: Metformin exerts differential metabolic effects in ovarian cancer cell lines

Abstract

Abstract Metformin is being actively repurposed for treatment of gynecologic malignancies including ovarian cancer, with various clinical trials underway. Metformin is known to alter the cancer cell metabolism, primarily by inhibiting oxidative phosphorylation and inducing glycolysis. Our aim was to investigate if metformin induces similar metabolic changes across ovarian cancer cells. Untargeted global metabolite assay, by ultra-high performance Liquid Chromatography and Gas Chromatography Mass Spectroscopy, was performed on A2780, C200, and SKOV3ip cell lines with and without metformin treatment (10mM for 48 hours). Per-metabolite comparisons were made across conditions. Interpretive analysis was performed using the KEGG molecular pathways (Kyoto Encyclopedia of Genes and Genomes) and the Ingenuity molecule library with a focus on energy pathways of glycolysis, oxidative phosphorylation and also other metabolic pathways. Additionally, glycolytic and mitochondrial respiration were measured using the Seahorse XFe Analyzer. Specific analysis of the glycolysis metabolites revealed that while glycolysis was increased by metformin in all the cells, the intracellular levels of glucose, lactose and pyruvate varied significantly across the cell lines and were differentially affected by metformin treatment. Metformin had little impact on the TCA cycle intermediates in the A2780 cells, which were significantly decreased in C200 and in contrast increased in SKOV3ip cells. Functional analysis showed the oxygen consumption rate to be significantly inhibited by metformin in all the three cell lines, while the increased fatty acid oxidation intermediates were observed across all the three cell lines albeit to a varying extent. Exploration of the global metabolite changes by metformin across the three cell lines revealed 57 common altered metabolites, of which 30 had consistent direction change, with 16 metabolite being up and 14 being downregulated by metformin treatment. Metabolite Set Enrichment analysis showed linolenic acid and methionine metabolism as most enriched in metabolites being increased by metformin, and RNA transcription and pyrimidine metabolism as most enriched in the metabolites downregulated by metformin treatment. Ingenuity analysis indicated cellular proliferation and signaling as the top common network pathway modulated by metformin. In conclusion metformin treatment had a significant and wide-spread effect on metabolism of ovarian cancer cell lines. While metformin resulted in certain consistent metabolic changes, it had cell line specific modulation on glycolysis and oxidative phosphorylation metabolites. These differential metabolic changes could indicate the degree of metformin response and suggest it to be context-dependent. Thus information about the cancer metabolism will aid in preclinical and clinical interpretation of metformin therapy in ovarian and other cancers. Citation Format: Adnan Munkarah, Laila Poisson, Seongho Kim, Jasdeep Chhina, Shailendra Giri, Ramandeep Rattan. Metformin exerts differential metabolic effects in ovarian cancer cell lines. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 11.