γ-Tocotrienol, a natural isoform of vitamin E, is a potent anticancer agent. Autophagy is a highly regulated process by which debris is eliminated from a cell, but can also play a role in cellular survival or death. The role of autophagy in mediating the anticancer effects of γ-tocotrienol is not clearly understood. This chapter reviews the mechanism(s) involved in γ-tocotrienol-induced autophagy in breast cancer cells. Treatment with γ-tocotrienol increased conversion of microtubule-associated protein, 1A/1B-light chain 3, from its cytosolic form (LC3B-I) to its lipidated form (LC3B-II), and the accumulation of autophagy-related proteins Beclin-1 (Atg6) and Atg5-Atg12. Additional studies confirmed that transfection with Beclin-1 siRNA or pretreated with 3-methyladenine (3-MA), an inhibitor of autophagy, blocked these effects. γ-Tocotrienol treatment also induced a time-responsive increase in autolysosome markers LAMP-1 and cathepsin-D, and pretreatment with bafilomycin A1 (Baf1), an inhibitor of late phase autophagy, blocked these effects and caused a significant reduction in γ-tocotrienol-induced cytotoxicity. γ-Tocotrienol also induced a decrease in ERK, an increase in p-38 and JNK activation, and endoplasmic reticulum (ER) stress apoptotic markers including phospho-PERK, phospho-elf2α, Bip, IRE1α, ATF-4, CHOP, and TRB3. In summary, γ-tocotrienol-induced autophagy is intimately involved in promoting ER-stress-mediated apoptosis in human breast cancer cells.
Part of the book: Autophagy in Current Trends in Cellular Physiology and Pathology
γ-Tocotrienol, a natural isoform within the vitamin E family of compounds, displays potent antiproliferative, apoptotic and reversal of epithelial-to-mesenchymal transition (EMT) activity against breast cancer using treatment doses that have little or no effect on normal cell viability. EMT is a route by which epithelial cells undergo various biochemical alterations leading to the acquisition of mesenchymal traits. Several aberrant signaling pathways are involved in EMT-dependent cancer metastasis. Specifically, dysregulation of the canonical Wnt and Hedgehog pathways are intimately involved in promoting breast cancer EMT and metastasis. Therefore, studies were conducted to examine effects of γ-tocotrienol on Wnt and Hedgehog signaling. Results from these studies demonstrate that γ-tocotrienol significantly inhibits canonical Wnt and Hedgehog signaling by inhibiting receptors, co-receptors and ligand expression, as well as inhibiting expression of cytosolic and nuclear signaling proteins within these pathways. Additional studies showed that γ-tocotrienol treatment increased the expression of negative regulators of both the Wnt and Hedgehog pathways. These findings demonstrate that γ-tocotrienol reversal of EMT is mediated, at least in part, through the inhibition of canonical Wnt and Hedgehog signaling, and strongly suggest that this form of vitamin E may provide significant benefit in the prevention and treatment of metastatic breast cancer.
Part of the book: Vitamin E in Health and Disease