Lipid Rafts and Fas/CD95 Signaling in Cancer Chemotherapy

Abstract

Cholesterol- and sphingolipid-rich membrane domains, termed lipid rafts, have been recently involved in the triggering of death receptor-mediated apoptosis. The alkyl-lysophospholipid analogue edelfosine was the first antitumor drug reported to induce apoptosis in cancer cells through co-clustering of lipid rafts and Fas/CD95 death receptor. Recruitment and aggregation of Fas/CD95 in lipid raft clusters was independent of its cognate ligand FasL/CD95L, and could be pharmacologically modulated. The adaptor molecule Fas-associated death domain protein (FADD) and procaspase-8 were also recruited into lipid rafts following edelfosine treatment, forming the death-inducing signaling complex (DISC), and hence these membrane microdomains can act as scaffolds for Fas/CD95 death signaling. Edelfosine accumulated in lipid rafts of cancer cells, altering raft protein and lipid composition. Subsequently, an increasing number of antitumor drugs have been found to induce apoptosis through recruitment of Fas/CD95 into membrane rafts, and some of these compounds accumulated in raft membrane domains. Additional downstream apoptotic signaling molecules have also been reported to be recruited into rafts following treatment of cancer cells with antitumor agents, thus facilitating protein-protein interactions and conveying apoptotic signals. On these grounds, lipid rafts have become an appealing and promising target for therapeutic intervention in cancer chemotherapy. Co-clustering of lipid rafts and Fas/CD95 signaling provides a new insight in the regulation of death receptor-mediated apoptosis, opening a new avenue in cancer therapy. In this regard, an increasing number of patents are dealing with the above insights in order to improve cancer treatment.

Pivotal Role of the Lipid Raft SK3–Orai1 Complex in Human Cancer Cell Migration and Bone Metastases

“…Kruskal-Wallis P = 0.089 into lipid rafts (24). Addition of Ohmline for 24 hours at 1 mmol/L had no effect on SK3 or Orai1 protein expression, but totally delocalized SK3 and Orai1 channels from lipid-raft fractions ( Fig.…”

Edelfosine lipid nanosystems overcome drug resistance in leukemic cell lines

“…Recent studies suggest that ET mainly accumulates in membrane lipid rafts and triggers the extrinsic apoptotic pathway throughout Fas/CD95 death receptor [9,10,23,27]. However, this mechanism might be diminished in the case of encapsulated drug, as it could be directed to different cell targets once inside the cell, promoting other drug actions and therefore overcoming resistance to the drug.…”

CD44 ligation with A3D8 antibody induces apoptosis in acute myeloid leukemia cells through binding to CD44s and clustering lipid rafts

“…Lipid raft clustering has been found to be involved in apoptosis induction through the activation of caspase-8 probably due to causing Fas aggregation. 19 Lipid rafts and the distribution of Fas were determined in NB4 cells after treatment with A3D8 at 2.5 μg/ml for 3 days using a confocal microscopy. Lipid rafts were assessed by lipid raft marker FITC-Ctx B according to the reported method.…”

“…17 Lipid raft clustering has been found to be essential for apoptosis induction by several agents, which involves the recruitment of Fas, Fas-associated death domain (FADD) and caspase-8. 18,19 Recently it has been found that CD44 is a down-stream target of fusion protein AML1-ETO formed due to t(8;21) translocation in AML cells. 20 AML cells with this fusion protein should be more effective than other types of leukemia cells to A3D8-induced apoptosis.…”