Abstract
Scope:
Docosahexaenoic acid (DHA) has been shown to exhibit anticancer actions in vitro and in vivo in a variety of cancers. Here, we investigated the role for DHA in inducing apoptosis in triple-negative breast cancer (TNBC) and studied the mechanisms of action.
Methods and results:
DHA induces apoptosis as detected by Annexin V-FITC/PI assay as well as induces cleavage of caspase-8 and -9, endoplasmic reticulum stress (ERS), and elevated levels of death receptor-5 (DR5) protein expression as detected by western blot assays. Chemical inhibitors of caspase-8 and -9 and small interfering RNAs (siRNAs) show DHA to induce ERS/CHOP/DR5-mediated caspase-8 and -9 dependent apoptosis. Furthermore, DHA induces elevated cellular levels of reactive oxygen species (ROS) and antioxidant; RRR-α-tocopherol (αT) blocked DHA-induced apoptotic events. In contrast to the antagonistic impact of αT, gamma-tocotrienol (γT3) was demonstrated to cooperate with DHA in inducing apoptotic events in TNBC cells.
Conclusion:
Data, for the first time, demonstrate that DHA induces apoptosis in TNBC cells via activation of ERS/CHOP/DR5-mediated caspase-8 and -9 dependent pro-apoptotic events, and that different forms of vitamin E exhibit distinct effects on DHA-induced apoptosis; namely, inhibition by αT and enhancement by γT3.
© 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / agonists
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Antineoplastic Agents / antagonists & inhibitors
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Antineoplastic Agents / metabolism*
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Antineoplastic Agents / pharmacology
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Antioxidants / metabolism*
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Antioxidants / pharmacology
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Apoptosis* / drug effects
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Breast Neoplasms / drug therapy
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Breast Neoplasms / metabolism*
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Caspase Inhibitors
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Caspases, Initiator / metabolism
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Cell Line, Tumor
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Chromans / pharmacology
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Cysteine Proteinase Inhibitors / pharmacology
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Docosahexaenoic Acids / agonists
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Docosahexaenoic Acids / antagonists & inhibitors
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Docosahexaenoic Acids / metabolism*
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Endoplasmic Reticulum Stress / drug effects
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Female
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism
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RNA Interference
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RNA, Messenger / metabolism
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RNA, Small Interfering
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Reactive Oxygen Species / antagonists & inhibitors
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Reactive Oxygen Species / metabolism
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Receptors, TNF-Related Apoptosis-Inducing Ligand / antagonists & inhibitors
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Receptors, TNF-Related Apoptosis-Inducing Ligand / genetics
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Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism
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Transcription Factor CHOP / antagonists & inhibitors
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Transcription Factor CHOP / genetics
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Transcription Factor CHOP / metabolism
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Vitamin E / analogs & derivatives*
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Vitamin E / metabolism
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Vitamin E / pharmacology
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alpha-Tocopherol / metabolism
Substances
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Antineoplastic Agents
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Antioxidants
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Caspase Inhibitors
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Chromans
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Cysteine Proteinase Inhibitors
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DDIT3 protein, human
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Neoplasm Proteins
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RNA, Messenger
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RNA, Small Interfering
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Reactive Oxygen Species
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Receptors, TNF-Related Apoptosis-Inducing Ligand
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Vitamin E
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Transcription Factor CHOP
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Docosahexaenoic Acids
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plastochromanol 8
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Caspases, Initiator
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alpha-Tocopherol