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Carcinogenesis Advance Access first published online on January 6, 2009
This version published online on January 9, 2009
Carcinogenesis, doi:10.1093/carcin/bgp008
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org

Death receptor pathways mediate targeted and non-targeted effects of ionizing radiations in breast cancer cells

Audrey Luce1, Aurélie Courtin1, Céline Levalois1, Sandrine Altmeyer-Morel1, Paul-Henri Romeo2, Sylvie Chevillard1,* and Jérôme Lebeau1,*

1 CEA, DSV, iRCM, SREIT, Laboratoire de Cancérologie Expérimentale (LCE), Fontenay-aux-Roses, F-92265, France
2 CEA, DSV, iRCM, SCSR, Laboratoire de recherche sur la Réparation et la Transcription dans les cellules Souches (LRTS), Fontenay-aux-Roses, F-92265, France

* To whom correspondence should be addressed. Dr J Lebeau, CEA, DSV, iRCM, SREIT, Laboratoire de Cancérologie Expérimentale (LCE), Fontenay-aux-Roses, F-92265, France. Tel: + 33 1 46 54 89 43; Fax: + 33 1 46 54 88 86; E-mail: jerome.lebeau{at}cea.fr or Dr S Chevillard, CEA, DSV, iRCM, SREIT, Laboratoire de Cancérologie Expérimentale (LCE), Fontenay-aux-Roses, F-92265, France. Tel: + 33 1 46 54 88 89; Fax: + 33 1 46 54 88 86; E-mail: sylvie.chevillard{at}cea.fr

Delayed cell death by mitotic catastrophe is a frequent mode of solid tumor cell death after {gamma}-irradiation, a widely used treatment of cancer. Whereas the mechanisms that underlie the early {gamma}-irradiation-induced cell death are well documented, those that drive the delayed cell death are largely unknown. Here we show that the Fas, TRAIL and TNF-{alpha} death receptor pathways mediate the delayed cell death observed after {gamma}-irradiation of breast cancer cells. Early after irradiation, we observe the increased expression of Fas, TRAIL-R and TNF-R that first sensitizes cells to apoptosis. Later, the increased expression of FasL, TRAIL and TNF-{alpha} permit the apoptosis engagement linked to mitotic catastrophe. Treatments with TNF-{alpha}, TRAIL or anti-Fas antibody, early after radiation exposure, induce apoptosis, while the neutralization of the three death receptors pathways impairs the delayed cell death. We also show for the first time that irradiated breast cancer cells excrete soluble forms of the three ligands which can induce the death of sensitive bystander cells. Overall, these results define the molecular basis of the delayed cell death of irradiated cancer cells and identify the death receptors pathways as crucial actors in apoptosis induced by targeted as well as non-targeted effects of ionizing radiation.

Received October 13, 2008; revised December 16, 2008; accepted December 22, 2008.


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