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Role of the ceramide-signaling pathways in ionizing radiation-induced apoptosis

Oncogene volume 22, pages 8645–8652 (2003)Cite this article

Abstract

Ionizing radiations (IR) exposure leads to damage on several cellular targets. How signals from different targets are integrated to determine the cell fate remains a controversial issue. Understanding the pathway(s) responsible(s) for the cell killing effect of the IR exposure is of prime importance in light of using radiations as anticancer agent or as diagnostic tool. In this study, we have established that IR-induced cell damage initiates two independent signaling pathways that lead to a biphasic intracellular ceramide increase. A transitory increase of ceramide is observed within minutes after IR exposure as a consequence of DNA damage-independent acid sphingomyelinase activation. Several hours after irradiation, a second wave of ceramide accumulation is observed depending on the DNA damage-dependent activation of ceramide synthase, which requires a signaling pathway involving ATM. Importantly, we have demonstrated that the late ceramide accumulation is also dependent on the first one and is rate limiting for the apoptotic process induced by IR. In conclusion, our observations suggest that ceramide is a major determinant of the IR-induced apoptotic process at the cross-point of different signal transduction pathways.

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Abbreviations

ASMase:

acid sphingomyelinase

A-T:

ataxia telangiectasia

ATM:

ataxia telangiectasia mutated gene

CS:

ceramide synthase

FB1:

fumonisin B1

IR:

ionizing radiations

NSM-ase:

neutral sphingomyelinase

PARP:

poly(ADP-ribose) poly-merase

SM:

sphingomyelin

TNFα:

tumor necrosis factor α

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Acknowledgements

We thank Dr A Stary, Dr C Guillouf and Dr G Laurent for helpful discussion and A Vervisch for cytometric analysis. This work was supported by grants from Electricité de France (EDF), and Association pour la Recherche sur le Cancer (ARC). Jean-Philippe Vit was a fellow from La Ligue Nationale Contre le Cancer (LNCC).

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  1. UPR 2169 CNRS, Institut Gustave Roussy IFR 54, 39, rue Camille Desmoulins, Villejuif Cedex, 94805, France

    Jean-Philippe Vit & Filippo Rosselli

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  1. Jean-Philippe Vit
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  2. Filippo Rosselli
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Correspondence to Filippo Rosselli.

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Vit, JP., Rosselli, F. Role of the ceramide-signaling pathways in ionizing radiation-induced apoptosis. Oncogene 22, 8645–8652 (2003). https://doi.org/10.1038/sj.onc.1207087

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