γ-Tocotrienol Promotes TRAIL-Induced Apoptosis through Reactive Oxygen Species/Extracellular Signal-Regulated Kinase/p53–Mediated Upregulation of Death Receptors

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of the tumor necrosis factor superfamily, is in clinical trials for cancer therapy, but its anticancer potential is limited by the development of resistance. We investigated the ability of tocotrienol (T3), an unsaturated vitamin E present in palm oil, rice bran, barley, oats, and wheat germ, to sensitize tumor cells to TRAIL. Results from esterase staining, colony formation, caspase activation, and sub-G 1 cell cycle arrest revealed that γ-T3 can sensitize human colon cancer cells to TRAIL. When examined for the mechanism, we found that γ-T3 significantly downregulated the expression of antiapoptotic proteins (c-IAP2 and Bcl-xL). We also found that γ-T3, but not tocopherol, induced the expression of the TRAIL receptors death receptor (DR)-4 and DR5. This induction was not cell type specific, as upregulation was also found in pancreatic, kidney, and leukemic cells. Upregulation of DRs by γ-T3 required the production of reactive oxygen species (ROS), and sequestering of ROS abolished both upregulation of the receptors and potentiation of TRAIL-induced apoptosis. Induction of DRs by γ-T3 also required activation of extracellular signal-regulated kinase 1 (ERK1), as silencing of ERK1 by specific siRNA abrogated the upregulation of TRAIL receptors. Further, induction of DRs by γ-T3 required the expression of p53 and Bax, as no induction of the receptors was found in colon cancer cells with deletion of these genes. Overall, our results show that γ-T3 sensitizes tumor cells to TRAIL by upregulating DRs through the ROS/ ERK/p53 pathway and by downregulating cell survival proteins. Mol Cancer Ther; 9(8); 2196-207. ©2010 AACR.

By-products of Rice Processing: An Overview of Health Benefits and Applications

“…For example, rice bran-derived tocotrienol inhibited tumour cell-induced angiogenesis in the mouse dorsal air sac (DOS) assay [111] and could promote tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) through the up regulation of death receptors in leukemic, kidney and pancreatic cells [112].…”

Tocotrienols fight cancer by targeting multiple cell signaling pathways

“…Thus, agents that up-regulate DRs have the potential to sensitize tumors to TRAIL. We investigated whether tocotrienol can promote TRAIL-induced apoptosis in colon cancer cells and found that it can sensitize human colon cancer cells to TRAIL (Kannappan et al 2010a). We also discovered that tocotrienol induced DR expression in a non-cell-type-specific fashion that is mediated through reactive oxygen species/ extracellular signal-regulated kinase/p53.…”

“…Evidence now suggests that tocotrienols have potentially greater physiologic functions than tocopherols do (Ahmad et al 2005;Ong et al 1993;Yu et al 1999;Kannappan et al 2010a;Kannappan et al 2010b). For instance, the ability to inhibit the inflammatory transcription factors nuclear factor (NF)-jB and signal transducer and activator of transcription (STAT) 3, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, mammalian DNA polymerases, and certain protein tyrosine kinases is unique to tocotrienols.…”

Why tocotrienols work better: insights into the in vitro anti-cancer mechanism of vitamin E

“…When investigated in cell model systems of breast and prostate cancer, two hormonedependent cancers with expected susceptibility to vitamin E interventions, HM-T3 show much stronger anti-proliferative and pro-apoptotic activity than TOH and a-T3. d-T3 is also the most potent form tested in pancreatic adenocarcinoma cells (Hussein and Mo 2009) while c-T3 was recently described to be the vitamer with anti-cancer activity in colon cancer cells (Kannappan, Ravindran et al;Xu et al 2009), which is another cancer form tentatively proposed as preventable by vitamin E therapy (Stone et al 2004), and in melanoma cells (Chang et al 2009). …”