Abstract 812: γ-tocotrienol induces mitophagy in breast cancer cells through activation of LKB1-AMPK pathway

Abstract

Abstract The dysregulation of glucose metabolism in cancer cells manifests as a characteristic phenomenon, referred to as the Warburg effect. Warburg effect is an over-reliance on aerobic glycolysis by cancer cells to meet the energy demand of proliferation. Previous studies have shown that γ-tocotrienol, a natural vitamin E derivative, inhibits aerobic glycolysis in human breast cancer cells through its modulation of key regulatory enzymes protein kinase B (Akt) and 5’-AMP activated kinase (AMPK). In the present study, we investigated the effects of γ-tocotrienol-induced activation of AMPK on mitochondrial dynamics in human breast cancer cells. Western blotting and immunocytochemistry analysis revealed that in human breast cancer cells MDA-MB-231 and T-47D, γ-tocotrienol removed the negative regulation of Akt on liver kinase B1 (LKB1), an upstream promoter of AMPK by increasing active complex formation and cytosolic localization of LKB1. In addition, γ-tocotrienol-induced activation of AMPK improved mitochondrial membrane potential through inhibition of uncoupling protein 1 (UCP1) as revealed by western blot analysis and mitochondrial membrane potential assay. High performance liquid chromatography (HPLC) analysis of NAD+/NADH ratio showed that γ-tocotrienol-induced AMPK activation improved the NAD+ ratio in human breast cancer cells, which indicates improving mitochondrial oxidative phosphorylation. In addition, γ-tocotrienol induced AMPK activation in human breast cancer cells causes increased mitochondrial fission, an indicator of mitophagy, as revealed by Western blot analysis of mitochondrial fission factor (MFF). In summary, these results show that γ-tocotrienol-induced AMPK activation modulates metabolic reprogramming in part by influencing the mitochondrial dynamics in human breast cancer cells. This work was supported in part by funds provided by the Louisiana Cancer Foundation. Citation Format: Venkatesh Dronamraju, Paul W. Sylvester. γ-tocotrienol induces mitophagy in breast cancer cells through activation of LKB1-AMPK pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 812.