γ‐Tocotrienol inhibits ErbB3‐dependent PI3K/Akt mitogenic signalling in neoplastic mammary epithelial cells

Samant, Ganesh V.; Sylvester, Paul W.

doi:10.1111/j.1365-2184.2006.00412.x

Cited by 101 publications

(97 citation statements)

References 23 publications

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“…T3 has the potency to induce apoptosis in a variety of cancer cell types (types 1-5). It has also been shown to downregulate the phosphatidylinositol 3-kinase/phosphoinositide-dependent kinase-1, AKT pathway (26,27) and c-myc expression (28) and to activate caspase-3, caspase-8, and caspase-9 (16,28,29). Despite this evidence, although more than 15,000 reports have been published on TPs, only 600 reports have been published on T3s, indicating a big gap in information available on the two types of vitamin E. Failure of recent clinical trials with TP against prostate cancer, costing more than US$143 million, further questions the usefulness of this vitamin.…”

Section: Introductionmentioning

confidence: 99%

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

Kannappan

Ravindran

Prasad

et al. 2010

Molecular Cancer Therapeutics

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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.

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Section: Introductionmentioning

confidence: 99%

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

Kannappan

Ravindran

Prasad

et al. 2010

Molecular Cancer Therapeutics

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“…EGFR and ERBB2 were not affected; the mechanism of the specific action on ERBB3 is not known. 433 Micro-RNA 125a reduced ERBB3 RNA and protein, activation of AKT and cell growth and invasiveness of SKBR3 mammary carcinoma cells. 434 Various other therapeutic approaches have been suggested.…”

Section: Discussionmentioning

confidence: 97%

The ERBB3 receptor in cancer and cancer gene therapy

2008

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ERBB3, a member of the epidermal growth factor receptor (EGFR) family, is unique in that its tyrosine kinase domain is functionally defective. It is activated by neuregulins, by other ERBB and nonERBB receptors as well as by other kinases, and by novel mechanisms. Downstream it interacts prominently with the phosphoinositol 3-kinase/AKT survival/mitogenic pathway, but also with GRB, SHC, SRC, ABL, rasGAP, SYK and the transcription regulator EBP1. There are likely important but poorly understood roles for nuclear localization and for secreted isoforms. Studies of ERBB3 expression in primary cancers and of its mechanistic contributions in cultured cells have implicated it, with varying degrees of certainty, with causation or sustenance of cancers of the breast, ovary, prostate, certain brain cells, retina, melanocytes, colon, pancreas, stomach, oral cavity and lung. Recent results link high ERBB3 activity with escape from therapy targeting other ERBBs in lung and breast cancers. Thus a wide and centrally important role for ERBB3 in cancer is becoming increasingly apparent. Several approaches for targeting ERBB3 in cancers have been tested or proposed. Small inhibitory RNA (siRNA) to ERBB3 or AKT is showing promise as a therapeutic approach to treatment of lung adenocarcinoma.

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“…18 More importantly, c-T3 promoted docetaxel-induced apoptosis in prostate cancer cells, 18 as well as docetaxel and dacarbazineinduced apoptosis in melanoma cells, 17 suggesting that it may be used as a potential chemosensitizing agent. Although T3 has been shown to regulate a number of signaling pathways, such as NK-kappaB 19 and PI3K, 20 the exact mechanisms underlying its anticancer effect are still largely unknown.…”

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confidence: 99%

Gamma‐tocotrienol as an effective agent in targeting prostate cancer stem cell‐like population

Luk

Yap²,

Chiu

et al. 2011

Intl Journal of Cancer

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Emerging evidence supports that prostate cancer originates from a rare subpopulation of cells, namely prostate cancer stem cells (CSCs). Conventional therapies for prostate cancer are believed to mainly target the majority of differentiated tumor cells but spare CSCs, which may account for the subsequent disease relapse after treatment. Therefore, successful elimination of CSCs may be an effective strategy to achieve complete remission from this disease. Gamma‐tocotrienols (γ‐T3) is one of the vitamin‐E constituents, which have been shown to have anticancer effects against a wide range of human cancers. Recently, we have reported that γ‐T3 treatment not only inhibits prostate cancer cell invasion but also sensitizes the cells to docetaxel‐induced apoptosis, suggesting that γ‐T3 may be an effective therapeutic agent against advanced stage prostate cancer. Here, we demonstrate for the first time that γ‐T3 can downregulate the expression of prostate CSC markers (CD133/CD44) in androgen‐independent prostate cancer cell lines (PC‐3 and DU145), as evident from Western blotting analysis. Meanwhile, the spheroid formation ability of the prostate cancer cells was significantly hampered by γ‐T3 treatment. In addition, pretreatment of PC‐3 cells with γ‐T3 was found to suppress tumor initiation ability of the cells. More importantly, although CD133‐enriched PC‐3 cells were highly resistant to docetaxel treatment, these cells were as sensitive to γ‐T3 treatment as the CD133‐depleted population. Our data suggest that γ‐T3 may be an effective agent in targeting prostate CSCs, which may account for its anticancer and chemosensitizing effects reported in previous studies.

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γ‐Tocotrienol inhibits ErbB3‐dependent PI3K/Akt mitogenic signalling in neoplastic mammary epithelial cells

Cited by 101 publications

References 23 publications

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

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

The ERBB3 receptor in cancer and cancer gene therapy

Gamma‐tocotrienol as an effective agent in targeting prostate cancer stem cell‐like population

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