Browsing by Subject "lipid rafts"

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    The influence of lipid rafts on aging and immunology
    (2009-08) Feng, Haoqi; Jolly, Christopher A.; Ciolino, Henry
    Lipid rafts are operationally defined as cholesterol-rich membrane microdomains resistant to solubilization in nonionic detergents at low temperatures. Lipid rafts, which are quite different in lipid composition from the surrounding membranes, are of great importance to signal transduction, protein sorting and membrane transport. They have been implicated in a range of biosynthetic and endocytic processes and systems-signaling, molecular trafficking, diseases as well as being involved in the immune, vascular, digestive and reproductive systems. Dietary nutrients like fatty acids and vitamins of different types also play a critical and decisive role in the regulation of lipid rafts.
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    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.