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Ceramide mediates caspase‐independent programmed cell death
Author(s) -
Thon Lutz,
Möhlig Heike,
Mathieu Sabine,
Lange Arne,
Bulanova Elena,
WinotoMorbach Supandi,
Schütze Stefan,
BulfonePaus Silvia,
Adam Dieter
Publication year - 2005
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.05-3726com
Subject(s) - ceramide , jurkat cells , lipid signaling , programmed cell death , microbiology and biotechnology , apoptosis , acid sphingomyelinase , caspase , biology , sphingolipid , caspase 8 , cancer research , t cell , immunology , receptor , biochemistry , immune system
Although numerous studies have implicated the sphingolipid ceramide in the induction of cell death, a causative function of ceramide in caspase‐dependent apoptosis remains a highly debated issue. Here, we show that ceramide is a key mediator of a distinct route to programmed cell death (PCD), i.e., caspase‐independent PCD. Under conditions where apoptosis is either not initiated or actively inhibited, TNF induces caspase‐independent PCD in L929 fibrosarcoma cells, NIH3T3 fibroblasts, human leukemic Jurkat T cells, and lung fibroblasts by increasing intracellular ceramide levels prior to the onset of cell death. Survival is significantly enhanced when ceramide accumulation is prevented, as demonstrated in fibroblasts genetically deficient for acid sphingomyelinase, in L929 cells overexpressing acid ceramidase, by pharmacological intervention, or by RNA interference. Jurkat cells deficient for receptor‐interacting protein 1 (RIP1) do not accumulate ceramide and therefore are fully resistant to caspase‐independent PCD whereas Jurkat cells overexpressing the mitochondrial protein Bcl‐2 are partially protected, implicating RIP1 and mitochondria as components of the ceramide death pathway. Our data point to a role of caspases (but not cathepsins) in suppressing the ceramide death pathway under physiological conditions. Moreover, clonogenic survival of tumor cells is clearly reduced by induction of the ceramide death pathway, promising additional options for the development of novel tumor therapies.—Thon, L., Möhlig, H., Mathieu, S., Lange, R., Bulanova, E., Winoto‐Morbach, S., Schütze, S., Bulfone‐Paus, S., Adam, D. Ceramide mediates caspase‐independent programmed cell death. FASEB J. 19, 1945–1956 (2005)