Abstract
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-β-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.
Highlights
The Fas death receptor (CD95 or APO-1) conveys apoptotic signals through binding to its cognate ligand, FasL (CD95L), making the interaction between FasL and Fas a potential tumor-fighting target
With a series of cell lines deficient in cell death receptors, we demonstrated that upon avicin D treatment, Fas translocates to lipid rafts, where it associates with Fas-associated death domain (FADD) and Caspase-8 to form death-inducing signaling complex (DISC), and mediates cell apoptosis
Avicin D treatment led to an elevated cleavage of Caspase-8, an important indicator of death receptor-induced apoptosis (Figure 1E)
Summary
The Fas death receptor (CD95 or APO-1) conveys apoptotic signals through binding to its cognate ligand, FasL (CD95L), making the interaction between FasL and Fas a potential tumor-fighting target. Unraveling the mechanisms could provide the basis for novel therapeutic strategies for various diseases and could aid in the development of new compounds able to exploit cytoplasmic triggers of apoptosis for clinical use. This is of importance in apoptosisdeficient disorders such as cancer [2] and autoimmune diseases [3]. Lipid rafts act as the linchpin from which a potent death signal is launched, suggesting a promising new target for anticancer therapeutics These findings have revealed a novel framework for the development of more targeted therapies leading to intracellular Fas activation and for the recruitment of downstream signaling molecules into Fas-enriched lipid rafts [2,3,4]
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