Involvement of de novo ceramide synthesis in gamma-tocopherol and gamma-tocotrienol-induced apoptosis in human breast cancer cells.

Archana Gopalan, Weiping Yu, Qing Jiang, Yumi Jang, Bob G Sanders, Kimberly Kline

Index: Mol. Nutr. Food. Res. 56(12) , 1803-11, (2012)

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Abstract

This study further examines mechanisms involved in the pro-apoptotic action of gamma-tocopherol (γT) and gamma-tocotrienol (γT3) in human breast cancer cell lines.γT upregulates phospho-JNK (pJNK), CCAAT/enhancer-binding protein homologous protein (CHOP), and death receptor-5 (DR5) protein expression as detected by Western blot assays. siRNA knockdown of JNK, CHOP, or DR5 shows that γT-induced apoptosis is JNK/CHOP/DR5 signaling dependent, which is similar to γT3-mediated apoptotic signaling. Furthermore, both γT and γT3 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 γT and γT3 to induce apoptosis as detected by Annexin V-FITC/PI assay and to activate JNK/CHOP/DR5 pro-apoptotic signaling thereby demonstrating the involvement of de novo ceramide synthesis in γT- and γT3-induced apoptosis.Taken together, data show that both γT and γT3 induce apoptosis via de novo ceramide synthesis dependent activation of JNK/CHOP/DR5 pro-apoptotic signaling.© 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.