Anticancer Effects of γ-Tocotrienol Are Associated with a Suppression in Aerobic Glycolysis

Abstract

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. Key words γ-tocotrienol; aerobic glycolysis; breast cancer; vitamin E; c-MycNormal differentiated nonproliferating cells metabolize glucose for fuel using glycolysis and oxidative phosphorylation. However, during hypoxic conditions glycolysis and oxidative phosphorylation becomes uncoupled and pyruvate is converted to lactate by anaerobic glycolysis.1,2) In contrast, cancer cells often metabolize glucose to lactate independently of oxygen availability using a process call aerobic glycolysis or the "Warburg effect," and this characteristic is considered to be a hallmark of neoplastic transformation.2-5) Although, aerobic glycolysis is less efficient than oxidative phosphorylation and requires the conversion of large quantities of glucose to lactate for the production of ATP, it provides intermediate precursors for the biosynthesis of macromolecules that are essential for cancer cell proliferation.

Targeting Glucose Transporters for Breast Cancer Therapy: The Effect of Natural and Synthetic Compounds

“…This member of the vitamin E family of compounds displays potent anticancer effects at doses having little or no effect on normal cell viability [164]. To test the role of glycolysis in the effect caused by γ-tocotrienol, Parajuli et al [165] used the MCF-7 breast cancer cell line. γ-tocotrienol was found to decrease MCF-7 cell growth, coincident with a concentration-dependent decrease in glucose consumption and lactate production.…”

γ-Tocotrienol Reversal of Epithelial-to-Mesenchymal Transition in Human Breast Cancer Cells is Mediated through a Suppression of Canonical Wnt and Hedgehog Signaling

“…Since γ-tocotrienol also induces a reversal of EMT in these cells and canonical Wnt and Hedgehog signaling pathways are involved in promoting EMT, it can be concluded that γ-tocotrienol inhibition of EMT is mediated by a corresponding reduction in canonical Wnt and Hedgehog signaling in malignant MDA-MB-231 human breast cancer cells. This hypothesis is further evidenced by the finding that γ-tocotrienol inhibition of Wnt and Hedgehog signaling and reversal of EMT is associated with a significant decrease in migration, invasion and stemness of these cells [12].…”

“…Studies have indicated that γ-tocotrienol induced inhibition of EGF-dependent proliferation of preneoplastic CL-S1 mouse mammary epithelial cells resulted from an inhibition of G-protein-mediated activation of adenylyl cyclase, cyclic adenosine monophosphate (cAMP) production, as well as a reduction in phosphorylated (activated) extracellular signal-regulated kinase 1/2 (ERK1 and ERK2) [33]. In addition to the inhibition of mitogenic signaling, γ-tocotrienol is known to inhibit numerous vital cellular functions including inhibition of cell cycle progression [13], mevalonate pathway [34,35], glycolysis [12], angiogenesis [36], and epithelial mesenchymal transition (EMT) [37].…”

“…PI3K/Akt [29] PKCα [32] MAPK [33] Cell cycle [13] Mevalonate pathway [34,35] Glycolysis [12] Angiogenesis [36] EMT [37] Lipid rafts [19] Table 2. Summary of some of the molecular targets associated with mediating the anticancer effects of tocotrienols.…”

“…Lipid rafts have been shown to be essential for Hedgehog signal transduction [10]. γ-Tocotrienol is a natural vitamin E isoform that displays potent anticancer activities [11][12][13]. Previous reports have clearly shown that γ-tocotrienol exerts antiproliferative and apoptotic activity against neoplastic mammary epithelial cells at treatment doses that had little or no effect on normal cell growth and viability [14,15].…”