Distinct roles of different forms of vitamin E in DHA-induced apoptosis in triple-negative breast cancer cells.
METHODS
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.


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.


CONCLUSIONS
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.
Department of Nutritional Sciences/A2703, University of Texas at Austin, Austin, TX 78712, USA.
Ailian
A
Xiong
Weiping
W
Yu
Richa
R
Tiwary
Bob G
BG
Sanders
Kimberly
K
Kline
D000970:Antineoplastic Agents / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D000975:Antioxidants / Q000378:metabolism* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D061945:Caspase Inhibitors; D053471:Caspases, Initiator / Q000378:metabolism; D045744:Cell Line, Tumor; D002839:Chromans / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004281:Docosahexaenoic Acids / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D024502:alpha-Tocopherol / Q000378:metabolism
D000970:Antineoplastic Agents; D000975:Antioxidants; D061945:Caspase Inhibitors; D002839:Chromans; D015853:Cysteine Proteinase Inhibitors; C497249:DDIT3 protein, human; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D014810:Vitamin E; D051742:Transcription Factor CHOP; D004281:Docosahexaenoic Acids; C013649:plastochromanol 8; D053471:Caspases, Initiator; D024502:alpha-Tocopherol