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The Tricyclodecan-9-yl-xanthogenate D609 Triggers Ceramide Increase and Enhances FasL-Induced Caspase-Dependent and -Independent Cell Death in T Lymphocytes
Team 4, Cancer Research Center of Toulouse, INSERM UMR1037, BP84225, 31432 Toulouse Cedex 4, France
Department of Cell Biology, Hematology and Immunology, Faculty of Pharmaceutical Sciences, Paul Sabatier University (Toulouse III), 31062 Toulouse, France
* Author to whom correspondence should be addressed.
Received: 1 June 2012; in revised form: 30 June 2012 / Accepted: 4 July 2012 / Published: 16 July 2012
Abstract: D609 is known to modulate death receptor-induced ceramide generation and cell death. We show that in Jurkat cells, non-toxic D609 concentrations inhibit sphingomyelin synthase and, to a lesser extent, glucosylceramide synthase, and transiently increase the intracellular ceramide level. D609 significantly enhanced FasL-induced caspase activation and apoptosis. D609 stimulated FasL-induced cell death in caspase-8-deficient Jurkat cells, indicating that D609 acts downstream of caspase-8. At high FasL concentration (500 ng/mL), cell death was significantly, but not completely, inhibited by zVAD-fmk, a broad-spectrum caspase inhibitor, indicating that FasL can activate both caspase-dependent and -independent cell death signaling pathways. FasL-induced caspase activation was abolished by zVAD-fmk, whereas ceramide production was only partially impaired. D609 enhanced caspase-independent ceramide increase and cell death in response to FasL. Also, D609 overcame zVAD-fmk-conferred resistance to a FasL concentration as low as 50 ng/mL and bypassed RIP deficiency. It is likely that mitochondrial events were involved, since Bcl-xL over-expression impaired D609 effects. In PHA-activated human T lymphocytes, D609 enhanced FasL-induced cell death in the presence or absence of zVAD-fmk. Altogether, our data strongly indicate that the inhibition of ceramide conversion to complex sphingolipids by D609 is accompanied by an enhancement of FasL-induced caspase-dependent and -independent cell death in T lymphocytes.
Keywords: CD95; apoptosis; necrosis; sphingomyelin synthase; glucosylceramide synthase; ALPS
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MDPI and ACS Style
Milhas, D.; Andrieu-Abadie, N.; Levade, T.; Benoist, H.; Ségui, B. The Tricyclodecan-9-yl-xanthogenate D609 Triggers Ceramide Increase and Enhances FasL-Induced Caspase-Dependent and -Independent Cell Death in T Lymphocytes. Int. J. Mol. Sci. 2012, 13, 8834-8852.
Milhas D, Andrieu-Abadie N, Levade T, Benoist H, Ségui B. The Tricyclodecan-9-yl-xanthogenate D609 Triggers Ceramide Increase and Enhances FasL-Induced Caspase-Dependent and -Independent Cell Death in T Lymphocytes. International Journal of Molecular Sciences. 2012; 13(7):8834-8852.
Milhas, Delphine; Andrieu-Abadie, Nathalie; Levade, Thierry; Benoist, Hervé; Ségui, Bruno. 2012. "The Tricyclodecan-9-yl-xanthogenate D609 Triggers Ceramide Increase and Enhances FasL-Induced Caspase-Dependent and -Independent Cell Death in T Lymphocytes." Int. J. Mol. Sci. 13, no. 7: 8834-8852.