Browsing by Subject "vitamin-e analog"

Now showing 1 - 2 of 2

Alpha-TEA-Induced Death Receptor Dependent Apoptosis Involves Activation of Acid Sphingomyelinase and Elevated Ceramide-Enriched Cell Surface Membranes
(2010-10) Li, Jing; Yu, Weiping; Tiwary, Richa; Park, Sook-Kyung; Xiong, Ailian; Sanders, Bob G.; Kline, Kimberly; Li, Jing; Yu, Weiping; Tiwary, Richa; Park, Sook-Kyung; Xiong, Ailian; Sanders, Bob G.; Kline, Kimberly
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.
Targeting Cholesterol-Rich Microdomains to Circumvent Tamoxifen-Resistant Breast Cancer
(2011) Tiwary, Richa; Yu, Weiping; Degraffenried, Linda A.; Sanders, Bob G.; Kline, Kimberly; Degraffenried, Linda A.; Sanders, Bob G.; Kline, Kimberly
Adjuvant treatment with tamoxifen substantially improves survival of women with estrogen-receptor positive (ER+) tumors. Tamoxifen resistance (TAMR) limits clinical benefit. RRR alpha tocopherol ether-linked acetic acid analogue (alpha-TEA) is a small bioactive lipid with potent anticancer activity. We evaluated the ability of alpha-TEA in the presence of tamoxifen to circumvent TAMR in human breast cancer cell lines. Methods: Two genotypically matched sets of TAM-sensitive (TAMS) and TAM-resistant (TAMR) human breast cancer cell lines were assessed for signal-transduction events with Western blotting, apoptosis induction with Annexin V-FITC/PI assays, and characterization of cholesterol-rich microdomains with fluorescence staining. Critical involvement of selected mediators was determined by using RNA interference and chemical inhibitors. Results: Growth-factor receptors (total and phosphorylated forms of HER-1 and HER-2), their downstream prosurvival mediators pAkt, pmTOR, and pERK1/2, phosphorylated form of estrogen receptor-alpha (pER-alpha at Ser-167 and Ser-118, and cholesterol-rich lipid microdomains were highly amplified in TAMR cell lines and enhanced by treatment with TAM. alpha-TEA disrupted cholesterol-rich microdomains, acted cooperatively with TAM to reduce prosurvival mediators, and induced DR5-mediated mitochondria-dependent apoptosis via an endoplasmic reticulum stress-triggered pro-death pJNK/CHOP/DR5 amplification loop. Furthermore, methyl-beta-cyclodextrin (M beta CD), a chemical disruptor of cholesterol rich microdomains, acted cooperatively with TAM to reduce prosurvival mediators and to induce apoptosis. Conclusions: Data for the first time document that targeting cholesterol-rich lipid microdomains is a potential strategy to circumvent TAMR, and the combination of alpha-TEA + TAM can circumvent TAMR by suppression of prosurvival signaling via disruption of cholesterol-rich lipid microdomains and activation of apoptotic pathways via induction of endoplasmic reticulum stress.