Cisplatin-induced CD95 redistribution into membrane lipid rafts of HT29 human colon cancer cells.
We have shown previously that the death receptor CD95 could contribute to anticancer drug-induced apoptosis of colon cancer cells. In addition, anticancer drugs cooperate with CD95 cognate ligand or agonistic antibodies to trigger cancer cell apoptosis. In the present study, we show that the anticancer drug cisplatin induces clustering of CD95 at the surface of the human colon cancer cell line HT29, an event inhibited by the inhibitor of acid sphingomyelinase (aSMase) imipramine. The cholesterol sequestering agent nystatin also prevents cisplatin-induced CD95 clustering and decreases HT29 cell sensitivity to cisplatin-induced apoptosis and the synergy between cisplatin and anti-CD95 agonistic antibodies. CD95, together with the adaptor molecule Fas-associated death domain and procaspase-8, is redistributed into cholesterol- and sphingolipid-enriched cell fractions after cisplatin treatment, suggesting plasma membrane raft involvement. Interestingly, nystatin prevents the translocation of the aSMase to the extracellular surface of plasma membrane and the production of ceramide, suggesting that these early events require raft integrity. In addition, nystatin prevents cisplatin-induced transient increase in plasma membrane fluidity that could be required for CD95 translocation. Together, these results demonstrate that cisplatin activates aSMase and induces ceramide production, which triggers the redistribution of CD95 into the plasma membrane rafts. Such redistribution contributes to cell death and sensitizes tumor cells to CD95-mediated apoptosis.
Lacour
Sandrine
S
Institut National de la Santé et de la Recherche Médicale U517, Dijon, France.
Hammann
Arlette
A
Grazide
Solène
S
Lagadic-Gossmann
Dominique
D
Athias
Anne
A
Sergent
Odile
O
Laurent
Guy
G
Gambert
Philippe
P
Solary
Eric
E
Dimanche-Boitrel
Marie-Thérèse
MT
D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002518:Ceramides / Q000096:biosynthesis; D002945:Cisplatin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004347:Drug Interactions; D019073:HT29 Cells; D006801:Humans; D008560:Membrane Fluidity / Q000187:drug effects; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism*; D009761:Nystatin / Q000494:pharmacology; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism*
D000970:Antineoplastic Agents; D002518:Ceramides; D019014:fas Receptor; D009761:Nystatin; D013108:Sphingomyelin Phosphodiesterase; D002945:Cisplatin