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Involvement of de novo ceramide synthesis in gamma‐tocopherol and gamma‐tocotrienol‐induced apoptosis in human breast cancer cells
Author(s) -
Gopalan Archana,
Yu Weiping,
Jiang Qing,
Jang Yumi,
Sanders Bob G.,
Kline Kimberly
Publication year - 2012
Publication title -
molecular nutrition and food research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.495
H-Index - 131
eISSN - 1613-4133
pISSN - 1613-4125
DOI - 10.1002/mnfr.201200350
Subject(s) - ceramide , apoptosis , chop , annexin , microbiology and biotechnology , fenretinide , biology , signal transduction , cancer research , chemistry , cell culture , biochemistry , retinoic acid , retinoid , genetics
Scope This study further examines mechanisms involved in the pro‐apoptotic action of gamma‐tocopherol (γ T ) and gamma‐tocotrienol (γ T 3) in human breast cancer cell lines. Methods and results γ T upregulates phospho‐ JNK (p JNK ), CCAAT /enhancer‐binding protein homologous protein ( CHOP ), and death receptor‐5 ( DR 5) protein expression as detected by W estern blot assays. si RNA knockdown of JNK , CHOP , or DR 5 shows that γ T ‐induced apoptosis is JNK / CHOP / DR 5 signaling dependent, which is similar to γ T 3‐mediated apoptotic signaling. Furthermore, both γ T and γ T 3 induce increased levels of cellular ceramides and dihydroceramides as determined by LC ‐ MS / MS analyses. Inhibition of de novo ceramide synthesis using chemical inhibitors blocked the ability of γ T and γ T 3 to induce apoptosis as detected by Annexin V ‐ FITC / PI assay and to activate JNK / CHOP / DR 5 pro‐apoptotic signaling thereby demonstrating the involvement of de novo ceramide synthesis in γ T ‐ and γ T 3‐induced apoptosis. Conclusion Taken together, data show that both γ T and γ T 3 induce apoptosis via de novo ceramide synthesis dependent activation of JNK / CHOP / DR 5 pro‐apoptotic signaling.