Aerobic glycolysis is an established hallmark of
cancer. Neoplastic cells display increased
glucose consumption and a corresponding increase in
lactate production compared to the normal cells. Aerobic glycolysis is regulated by the phosphatidylinositol-3-kinase (PI3K)/Akt/
mammalian target of rapamycin (mTOR) signaling pathway, as well as by oncogenic
transcription factors such as c-Myc and
hypoxia inducible factor 1α (HIF-1α). γ-
Tocotrienol is a natural
isoform within the
vitamin E family of compounds that displays potent antiproliferative and apoptotic activity against a wide range of
cancer cell types at treatment doses that have little or no effect on normal cell viability. Studies were conducted to determine the effects of γ-
tocotrienol on aerobic glycolysis in mouse +SA and human MCF-7
breast cancer cells. Treatment with γ-
tocotrienol resulted in a dose-responsive inhibition of both +SA and MCF-7 mammary
tumor cell growth, and induced a relatively large reduction in
glucose utilization, intracellular
ATP production and extracellular
lactate excretion. These effects were also associated with a large decrease in
enzyme expression levels involved in regulating aerobic glycolysis, including
hexokinase-II,
phosphofructokinase,
pyruvate kinase M2, and
lactate dehydrogenase A. γ-
Tocotrienol treatment was also associated with a corresponding reduction in the levels of phosphorylated (active) Akt, phosphorylated (active) mTOR, and c-Myc, but not HIF-1α or
glucose transporter 1 (GLUT-1). In summary, these findings demonstrate that the antiproliferative effects of γ-
tocotrienol are mediated, at least in the part, by the concurrent inhibition of Akt/mTOR signaling, c-Myc expression and aerobic glycolysis.