期刊
CANCER CELL INTERNATIONAL
卷 10, 期 -, 页码 -出版社
BMC
DOI: 10.1186/1475-2867-10-40
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资金
- Public Health Service [CA59739]
- Clayton Foundation for Research
- National Institute of Environmental Health Sciences Center [ES007784]
- Center for Molecular and Cellular Toxicology at the University of Texas at Austin
- NIEHS/NIH [T32 ES07247]
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.
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