Lipid raft-mediated Fas/CD95 apoptotic signaling in leukemic cells and normal leukocytes and therapeutic implications

Abstract

Plasma membrane is now recognized to contain tightly packed cholesterol/sphingolipid-rich domains, known as lipid or membrane rafts, which are more ordered than the surrounding lipid bilayer. Lipid rafts are crucial for the compartmentalization of signaling processes in the membrane, mostly involved in cell survival and immune response. However, in the last 15 years, a large body of evidence has also identified raft platforms as scaffolds for the recruitment and clustering of death receptor Fas/CD95 and downstream signaling molecules, leading to the concept of death-promoting lipid rafts. This raft-Fas/CD95 coclustering was first described at the early 2000s as the underlying mechanism for the proapoptotic action of the alkylphospholipid analog edelfosine in leukemic cells, hence facilitating protein-protein interactions and conveying apoptotic signals independently of Fas/CD95 ligand. Edelfosine induces apoptosis in hematologic cancer cells and activated T-lymphocytes. Fas/CD95 raft coclustering is also promoted by Fas/CD95 ligand, agonistic Fas/CD95 antibodies, and additional antitumor drugs. Thus, death receptor recruitment in rafts is a physiologic process leading to cell demise that can be pharmacologically modulated. This redistribution and local accumulation of apoptotic molecules in membrane rafts, which are usually accompanied by displacement of survival signaling molecules, highlight how alterations in the apoptosis/survival signaling balance in specialized membrane regions modulate cell fate. Membrane rafts might also modulate apoptotic and nonapoptotic death receptor signaling. Here, we discuss the role of lipid rafts in Fas/CD95-mediated apoptotic cell signaling in hematologic cancer cells and normal leukocytes, with a special emphasis on their involvement as putative therapeutic targets in cancer and autoimmune diseases.

Lipid rafts as signaling hubs in cancer cell survival/death and invasion: implications in tumor progression and therapy

“…Clustering of lipid rafts to form large raft platforms provides a mechanism by which an increasing number of proteins can be recruited to exert their functions in a safe and favorable way. These raft platforms provide the appropriate scaffolds for the recruitment of receptors, adaptor proteins and other signaling molecules to generate dynamic headquarters to control what gets in and what stays out, thus constituting signaling units from which signals can be delivered to exert and modulate various cell functions (21, 23, 82, 84,85). A key hallmark of membrane rafts lies in the physical segregation of proteins in lipid rafts that may modulate the accessibility of proteins to regulatory or effector molecules (67).…”

“…(154,193,199,200). Disruption of rafts by membrane cholesterol depletion abolishes DISC formation and Fas/CD95-mediated cell death (85,98,199,200). Fas/CD95 localization to lipid rafts and efficient cell death signaling require S-palmitoylation of human Fas/CD95 at cysteine residue 199 (Cys-194 in mouse), at the membrane proximal intracellular region, of the death receptor (201,202).…”

“…Because the addition of physiological ligands also induced death receptor translocation to lipid rafts (196), we concluded that edelfosine treatment exacerbated a physiological process that leads to apoptotic cell death. Furthermore, edelfosine was able to promote recruitment of Fas/CD95 in rafts and subsequent apoptosis in a number of cells that were resistant to the physiological ligand FasL/CD95L (82, 184), thus triggering a new way to activate Fas/CD95, independently of the natural ligand (85,154,197,198). It might be envisaged that pharmacological activation of Fas/CD95 system might bypass processes that could block the physiological death receptor stimulation, thus promoting a response in resistant cells.…”

Pingmu Decoction Induces Orbital Preadipocytes Apoptosis In Vitro

“…However, its apoptotic effect on differentiated adipocytes from GO patients remains uncharacterized. Intracellular pathways mediated by Fas/Fas L in mammals can induce apoptosis [13, 14]. We cultured orbital preadipocytes from patients by the tissue explant method and differentiated them into orbital adipocytes.…”

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“…Cholesterol is necessary to the structure and function of caveolae and clathrin-coated pits, enabling the endocytotic activity [3,4]. In recent decades, increasing lines of evidence show that lipid rafts, which are membrane micro domains assemble glycosphingolipids, protein receptors and kinases, preferentially associate with cholesterol and saturated lipids in driving a wide variety of cellular signaling pathways [5,6]. Not only in normal cellular and physiological functions, intracellular cholesterol homoeostasis once deregulated can be responsible for the development of malignancies through decreasing chemotherapeutic susceptibility and increasing resistance in cancer cells, inhibiting the release of mitochondrial cell death-promoting molecules, activating survival kinases and many other mechanisms [7][8][9].…”