Avicins， a family of triterpene electrophiles originally identified as potent inhibitors of tumor cell growth， have been shown to be pleiotropic compounds that also possess antioxidant， anti-mutagenic， and anti-inflammatory activities. We previously showed that Jurkat cells， which express a high level of Fas， are very sensitive to treatment with avicins. Thus， we hypothesized that avicins may induce cell apoptosis by activation of the Fas pathway. By using a series of cell lines deficient in cell death receptors， we demonstrated that upon avicin D treatment， Fas translocates to the cholesterol- and sphingolipid-enriched membrane microdomains known as lipid rafts. In the lipid rafts， Fas inte... More
Avicins， a family of triterpene electrophiles originally identified as potent inhibitors of tumor cell growth， have been shown to be pleiotropic compounds that also possess antioxidant， anti-mutagenic， and anti-inflammatory activities. We previously showed that Jurkat cells， which express a high level of Fas， are very sensitive to treatment with avicins. Thus， we hypothesized that avicins may induce cell apoptosis by activation of the Fas pathway. By using a series of cell lines deficient in cell death receptors， we demonstrated that upon avicin D treatment， Fas translocates to the cholesterol- and sphingolipid-enriched membrane microdomains known as lipid rafts. In the lipid rafts， Fas interacts with Fas-associated death domain (FADD) and Caspase-8 to form death-inducing signaling complex (DISC) and thus mediates cell apoptosis. Interfering with lipid raft organization by using a cholesterol-depleting compound， methyl-beta-cyclodextrin， not only prevents the clustering of Fas and its DISC complex but also reduces the sensitivity of the cells to avicin D. Avicin D activates Fas pathways independent of the association between extracellular Fas ligands and Fas receptors. A deficiency in Fas and its downstream signaling molecules leads to the resistance of the cells to avicin D treatment. Taken together， our results demonstrate that avicin D triggers the redistribution of Fas in the membrane lipid rafts， where Fas activates receptor-mediated cell death.
