Int. J. Mol. Sci. 2012, 13(7), 8834-8852; doi:10.3390/ijms13078834
Article

The Tricyclodecan-9-yl-xanthogenate D609 Triggers Ceramide Increase and Enhances FasL-Induced Caspase-Dependent and -Independent Cell Death in T Lymphocytes

1 Team 4, Cancer Research Center of Toulouse, INSERM UMR1037, BP84225, 31432 Toulouse Cedex 4, France 2 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
(This article belongs to the collection Programmed Cell Death and Apoptosis)
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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.

AMA 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. International Journal of Molecular Sciences. 2012; 13(7):8834-8852.

Chicago/Turabian Style

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.

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