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Role Of Caspase-8 Activation In Mediating Vitamin E-Induced Apoptosis In Murine Mammary Cancer Cells
Sumit J Shah, A. Gapor, P. Sylvester
Published 2003 · Biology, Medicine
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The vitamin E family of compounds is divided into two subgroups, tocopherols and tocotrienols. However, tocotrienols display more potent apoptotic activity in mammary cancer cells. Although the mechanism(s) mediating tocotrienol-induced apoptosis is presently unknown, apoptosis is carried out by activation of initiator caspases (caspase-8 or -9) that subsequently activate effector caspases (caspase-3, -6, or -7). Studies were conducted to determine whether tocotrienol-induced apoptosis is mediated by activation of the caspase-8 and/or caspase-9 pathway. Highly malignant +SA mouse mammary epithelial cells were grown in culture and maintained on serum-free media. Treatment with tocotrienol-rich-fraction of palm oil (TRF) and γ-tocotrienol, but not α-tocopherol, induced a dose-dependent decrease in +SA cell viability. TRF- and γ-tocotrienol-induced cell death resulted from apoptosis, as determined by DNA fragmentation and positive TUNEL assay staining. Additional studies showed that treatment with 50 μM TRF or 20 μM γ-tocotrienol increased intracellular activity and levels of processed caspase-8 and -3 but not caspase-9. Furthermore, treatment with specific caspase-8 or -3 inhibitors, but not caspase-9 inhibitor, completely blocked the tocotrienol-induced apoptosis in +SA cells. These findings demonstrate that tocotrienol-induced apoptosis in +SA mammary cancer cells is mediated through activation of the caspase-8 signaling pathway and is independent of caspase-9 activation.
This paper references
dl‐α‐tocopherol induces apoptosis in erythroleukemia, prostate, and breast cancer cells
G. Sigounas (1997)
Protein complexes activate distinct caspase cascades in death receptor and stress-induced apoptosis.
S. B. Bratton (2000)
Selection and characterization in culture of mammary tumor cells with distinctive growth properties in vivo.
K. Danielson (1980)
Antiproliferative and apoptotic effects of tocopherols and tocotrienols on preneoplastic and neoplastic mouse mammary epithelial cells.
B. S. Mcintyre (2000)
Activation of extracellular signal-regulated kinase and c-Jun-NH(2)-terminal kinase but not p38 mitogen-activated protein kinases is required for RRR-alpha-tocopheryl succinate-induced apoptosis of human breast cancer cells.
W. Yu (2001)
Vitamin E inhibition of normal mammary epithelial cell growth is associated with a reduction in protein kinase Cα activation
P. Sylvester (2001)
Caspases: enemies within.
N. Thornberry (1998)
Comparative effects of different animal and vegetable fats fed before and during carcinogen administration on mammary tumorigenesis, sexual maturation, and endocrine function in rats.
P. Sylvester (1986)
Induction of apoptosis in human breast cancer cells by tocopherols and tocotrienols.
W. Yu (1999)
The CD95 (APO-1/Fas) and the TRAIL (APO-2L) apoptosis systems.
H. Walczak (2000)
Cleavage of BID by Caspase 8 Mediates the Mitochondrial Damage in the Fas Pathway of Apoptosis
H. Li (1998)
Vitamin E succinate (VES) induces Fas sensitivity in human breast cancer cells: role for Mr 43,000 Fas in VES-triggered apoptosis.
W. Yu (1999)
Caspase-3-dependent Cleavage of Bcl-2 Promotes Release of Cytochrome c *
D. Kirsch (1999)
Vitamin E: function and metabolism
R. Brigelius-Flohé (1999)
Serial killers: ordering caspase activation events in apoptosis
EA Slee (1999)
The Bcl-2 protein family.
L. O’Connor (1999)
Mechanism of α-tocopheryl succinate-induced apoptosis of promyelocytic leukemia cells
Shinji Yamamoto (2000)
Vitamin E: mechanisms of action as tumor cell growth inhibitors.
K. Kline (2001)
Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications.
H. Towbin (1979)
α‐Tocopheryl succinate‐induced apoptosis in Jurkat T cells involves caspase‐3 activation, and both lysosomal and mitochondrial destabilisation
J. Neuzil (1999)
Metastatic potential of hyperplastic alveolar nodule derived mouse mammary tumor cells following intravenous inoculation.
L. Anderson (1981)
Evidence for role of transforming growth factor-β in RRR-α-tocopheryl succinate-induced apoptosis of human MDA-MB-435 breast cancer cells
W. Yu (1997)
Evidence for role of transforming growth factor-beta in RRR-alpha-tocopheryl succinate-induced apoptosis of human MDA-MB-435 breast cancer cells.
W. Yu (1997)
Substrate Specificities of Caspase Family Proteases*
R. Talanian (1997)
Mammalian caspases: structure, activation, substrates, and functions during apoptosis.
W. Earnshaw (1999)
Mechanism of alpha-tocopheryl succinate-induced apoptosis of promyelocytic leukemia cells.
S. Yamamoto (2000)
Distinct Caspase Cascades Are Initiated in Receptor-mediated and Chemical-induced Apoptosis*
X. Sun (1999)
Membrane oligomerization and cleavage activates the caspase-8 (FLICE/MACHalpha1) death
DA Martin (1998)
Apoptosis: A Basic Biological Phenomenon with Wide-ranging Implications in Tissue Kinetics
J. Kerr (1972)
Introduction: nutritional aspects of palm oil.
R. Cottrell (1991)
Fas-signaling and effects on receptor tyrosine kinase signal transduction in human breast epithelial cells.
K. Shen (1997)
Protective role of vitamin E in biological systems.
L. Packer (1991)
Apoptosis signaling by death receptors.
K. Schulze-Osthoff (1998)
Bax membrane insertion during Fas(CD95)-induced apoptosis precedes cytochrome c release and is inhibited by Bcl-2
K. Murphy (1999)
The selective cytotoxic effect of carotenoids and alpha-tocopherol on human cancer cell lines in vitro.
J. Schwartz (1992)
Caspase-8 Activation and Bid Cleavage Contribute to MCF7 Cellular Execution in a Caspase-3-dependent Manner during Staurosporine-mediated Apoptosis*
D. Tang (2000)
Membrane Oligomerization and Cleavage Activates the Caspase-8 (FLICE/MACHα1) Death Signal*
D. Martin (1998)
Vitamin E and breast cancer: a review.
G. Kimmick (1997)
Activation of Extracellular Signal-regulated Kinase and c-Jun-NH2-terminal Kinase but not p38 Mitogen-activated Protein Kinases Is Required for RRR-α-Tocopheryl Succinate-induced Apoptosis of Human Breast Cancer Cells
W. Yu (2001)
Fatty acid modulation of epidermal growth factor-induced mouse mammary epithelial cell proliferation in vitro.
P. Sylvester (1994)
Bid-induced Conformational Change of Bax Is Responsible for Mitochondrial Cytochrome c Release during Apoptosis
S. Desagher (1999)
Fas expression and function in normal and malignant breast cell lines.
M. Keane (1996)
Tropical oils: nutritional and scientific issues.
C. Elson (1992)
Vitamin E succinate inhibits proliferation of BT-20 human breast cancer cells: increased binding of cyclin A negatively regulates E2F transactivation activity.
J. Turley (1997)
Cytochrome c and dATP-Dependent Formation of Apaf-1/Caspase-9 Complex Initiates an Apoptotic Protease Cascade
Peng Li (1997)
Tropical oils: Nutritional and scientific issues
Elson Ce (1992)
[Mitochondria and apoptosis].
Y. Li (2000)
Apoptosis in mammary gland and cancer.
R. Kumar (2000)
dl-alpha-tocopherol induces apoptosis in erythroleukemia, prostate, and breast cancer cells.
G. Sigounas (1997)
Distinct stages of cytochrome c release from mitochondria: evidence for a feedback amplification loop linking caspase activation to mitochondrial dysfunction in genotoxic stress induced apoptosis
Q. Chen (2000)
Relationship between epidermal growth factor receptor levels, autophosphorylation and mitogenic‐responsiveness in normal mouse mammary epithelial cells in vitro
B. S. Mcintyre (1995)
This paper is referenced by
Antiproliferative and Apoptotic Effects of Tocotrienols on Normal and Neoplastic Mammary Epithelial Cells
P. Sylvester (2008)
γ-Tocotrienol Inhibits Nuclear Factor-κB Signaling Pathway through Inhibition of Receptor-interacting Protein and TAK1 Leading to Suppression of Antiapoptotic Gene Products and Potentiation of Apoptosis*
K. S. Ahn (2007)
Anti‐proliferative effects of γ‐tocotrienol on mammary tumour cells are associated with suppression of cell cycle progression
G. V. Samant (2010)
Fenugreek, a naturally occurring edible spice, kills MCF-7 human breast cancer cells via an apoptotic pathway.
K. K. Khoja (2011)
Tumor suppressive effects of tocotrienol in vivo and in vitro.
S. Wada (2005)
Intracellular signaling mechanisms mediating the antiproliferative and apoptotic effects of gamma-tocotrienol in neoplastic mammary epithelial cells.
P. Sylvester (2005)
Preparation, characterization, and anticancer effects of simvastatin-tocotrienol lipid nanoparticles.
Hazem Ali (2010)
Tocotrienols in Plants: Sources and Importance
L. Harinantenaina (2008)
Endoplasmic reticulum stress mediates γ-tocotrienol-induced apoptosis in mammary tumor cells
V. Wali (2009)
Vitamin E and apoptosis.
P. Sylvester (2007)
γ-Tocotrienol inhibits angiogenesis of human umbilical vein endothelial cell induced by cancer cell.
Y. Li (2011)
Induction of Apoptosis in SNU-16 Human Gastric Cancer Cells by the Chloroform Fraction of an Extract of Dangyuja (Citrus grandis Leaves
Jeong Yong Moon (2009)
The potential therapeutic role of Fenugreek saponin against Alzheimer's disease: Evaluation of apoptotic and acetylcholinesterase inhibitory activities -
W. Khalil (2016)
Extraction and Purification of Gamma-Tocotrienol from Rice Bran Oil Deodorizer Distillate
Mary Kordsmeier (2013)
γ-Tocotrienol-induced autophagy in malignant mammary cancer cells
R. Tiwari (2014)
Alpha-tocopherol-mediated caspase-3 up-regulation enhances susceptibility to apoptotic stimuli.
N. Miyoshi (2005)
Multitargeted therapy of cancer by tocotrienols.
K. Nesaretnam (2008)
Catechin hydrate suppresses MCF-7 proliferation through TP53/Caspase-mediated apoptosis
A. Alshatwi (2010)
Tocotrienols: Vitamin E beyond tocopherols.
C. Sen (2006)
Anticancer properties of tocotrienols: A review of cellular mechanisms and molecular targets
M. Montagnani Marelli (2019)
gamma-Tocotrienol induces mitochondria-mediated apoptosis in human gastric adenocarcinoma SGC-7901 cells.
Wenguang Sun (2009)
Tocotrienol in Human Pancreatic Cancer
M. Malafa (2012)
3, 3′-Diindolylmethane-encapsulated chitosan nanoparticles accelerate molecular events during chemical carcinogen-induced mammary cancer in Sprague Dawley rats
S. Isabella (2019)
Palm tocotrienols inhibit proliferation of murine mammary cancer cells and induce expression of interleukin-24 mRNA.
K. R. Selvaduray (2010)
Preferential radiation sensitization of prostate cancer in nude mice by nutraceutical antioxidant gamma-tocotrienol.
K. S. Kumar (2006)
γ‐Tocotrienol reversal of epithelial‐to‐mesenchymal transition in human breast cancer cells is associated with inhibition of canonical Wnt signalling
R. A. Ahmed (2016)
Tocotrienol-Induced Caspase-8 Activation is Unrelated to Death Receptor Apoptotic Signaling in Neoplastic Mammary Epithelial Cells
Sumit J Shah (2004)
Chemoprevention of tocotrienols: the mechanism of antiproliferative effects.
S. Wada (2009)
Sesamin synergistically potentiates the anticancer effects of γ-tocotrienol in mammary cancer cell lines.
M. Akl (2013)
Vitamin E and cancer: an update on the emerging role of γ and δ tocotrienols
C. Constantinou (2019)
Tocotrienols and cancer: beyond antioxidant activity.
K. Nesaretnam (2007)See more