Metformin Suppresses The Growth And Modulates The Metabolic Profiles Of Pancreatic Cancer Cells Under Hypoxia In An Ikk Alpha-Dependent Manner

Abstract Nuclear factor-βB; (NF-κB) controls a range of genes involved in inflammation, cell survival, growth and apoptosis. The dysregulated NF-κB pathway has been found to be involved in carcinogenesis and cancer progression. An IKKα-deleted mouse pancreatic cancer cell line was generated using a lentiviral construct with an shRNA. We investigated the effects of metformin, an anti-diabetic drug, on the cell proliferation and metabolism of these cells, under normoxic and hypoxic conditions. A high dose (5 mM) of metformin under normoxic conditions suppressed the growth of both wild-type and IKKα knockdown cell types; however, under hypoxic conditions IKKα knockdown cells were more sensitive to treatment than their wild-type counterpart (p < 0.001). Metabolic assays revealed that metformin treatment under normoxic conditions decreased the oxidative phosphorylation (OXPHOS) whilst increasing the lactate production of both cell types to similar levels. Under hypoxia, metformin treatment of both cancer cells resulted in decreased OXPHOS, with a more profound effect on the IKKα knockdown cells, and a significant decrease in lactate production in the IKKα knockdown cells only (p < 0.001). We believe our findings have implications for understanding the molecular mechanisms of metformin as a therapeutic agent in cancer treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3209. doi:1538-7445.AM2012-3209