Alpha-TEA-Induced Death Receptor Dependent Apoptosis Involves Activation of Acid Sphingomyelinase and Elevated Ceramide-Enriched Cell Surface Membranes

Access full-text files




Li, Jing
Yu, Weiping
Tiwary, Richa
Park, Sook-Kyung
Xiong, Ailian
Sanders, Bob G.
Kline, Kimberly

Journal Title

Journal ISSN

Volume Title



Background: Alpha-tocopherol ether-linked acetic acid (alpha-TEA), an analog of vitamin E (RRR-alpha-tocopherol), is a potent and selective apoptosis-inducing agent for human cancer cells in vivo and in vitro. alpha-TEA induces apoptosis via activation of extrinsic death receptors Fas (CD95) and DR5, JNK/p73/Noxa pathways, and suppression of antiapoptotic mediators Akt, ERK, c-FLIP and survivin in breast, ovarian and prostate cancer cells. Results: In this study, we demonstrate that alpha-TEA induces the accumulation of cell surface membrane ceramide, leading to co-localization with Fas, DR5, and FADD, followed by activation of caspases-8 and -9 and apoptosis in human MDA-MB-231 breast cancer cells. alpha-TEA treatment leads to increased acid sphingomyelinase (ASMase) activity by 30 min, peaking at 4 hrs, which is correlated with ASMase translocation from cytosol to the cell surface membrane. Functional knockdown of ASMase with either the chemical inhibitor, desipramine, or siRNA markedly reduces alpha-TEA-induced cell surface membrane accumulation of ceramide and its co-localization with Fas, DR5, and FADD, cleavage of caspases-8 and -9 and apoptosis, suggesting an early and critical role for ASMase in alpha-TEA-induced apoptosis. Consistent with cell culture data, immunohistochemical analyses of tumor tissues taken from alpha-TEA treated nude mice bearing MDA-MB-231 xenografts show increased levels of cell surface membrane ceramide in comparison to tumor tissues from control animals. Conclusion: Taken together, these studies demonstrate that ASMase activation and membrane ceramide accumulation are early events contributing to alpha-TEA-induced apoptosis in vitro and perhaps in vivo.


LCSH Subject Headings


Li, Jing, Weiping Yu, Richa Tiwary, Sook-Kyung Park, Ailian Xiong, Bob G. Sanders, and Kimberly Kline. "?-TEA-induced death receptor dependent apoptosis involves activation of acid sphingomyelinase and elevated ceramide-enriched cell surface membranes." Cancer cell international, Vol. 10, No. 1 (Oct., 2010): 1.