Ionizing radiation modulates the TRAIL death-inducing signaling complex, allowing bypass of the mitochondrial apoptosis pathway.

Ionizing radiation modulates the TRAIL death-inducing signaling complex, allowing bypass of the mitochondrial apoptosis pathway. Research Abstract Details 

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Ionizing radiation modulates the TRAIL death-inducing signaling complex, allowing bypass of the mitochondrial apoptosis pathway. Abstract Text:

I Verbrugge,E de Vries,S W G Tait,E H J Wissink,H Walczak,M Verheij,J Borst,

In many tumor cell types, ionizing radiation (IR) or DNA-damaging anticancer drugs enhance sensitivity to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis, which is of great clinical interest. We have investigated the molecular mechanism underlying the response to combined modality treatment in p53-mutant Jurkat T leukemic cells overexpressing Bcl-2. These cells are largely resistant to individual treatment with TRAIL or IR, but sensitive to combined treatment, in vitro as well as in vivo. We demonstrate that IR and DNA-damaging anticancer drugs enable TRAIL receptor-2 and CD95/Fas to bypass the mitochondrial pathway for effector caspase activation. This was validated by RNA interference for Bax and Bak and by overexpression of dominant-negative Caspase-9. Improved effector caspase activation was neither caused by altered expression of proapoptotic components nor by impaired activity of inhibitor of apoptosis proteins or nuclear factor-kappaB signaling. Rather, we found that pretreatment of cells with IR caused quantitative and qualitative changes in death receptor signaling. It strongly improved the capacity of ligand-bound receptors to recruit FADD and activate Caspase-8 and -10 in the death-inducing signaling complex, while c-FLIP(L) levels were unaffected.

Ionizing radiation modulates the TRAIL death-inducing signaling complex, allowing bypass of the mitochondrial apoptosis pathway. Publishing Authors By Initials

I Verbrugge,E de Vries,SW Tait,EH Wissink,H Walczak,M Verheij,J Borst,

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Ionizing radiation modulates the TRAIL death-inducing signaling complex, allowing bypass of the mitochondrial apoptosis pathway. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Oncogene

VOLUME: 27

Page Numbers: 574-84

Journal Abbreviation: Oncogene

ISSN: 1476-5594

DAY: 6

MONTH: 08

YEAR: 2007

Ionizing radiation modulates the TRAIL death-inducing signaling complex, allowing bypass of the mitochondrial apoptosis pathway. Information

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LANGUAGE: eng

NlmUniqueID: 8711562

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Grant and Affiliation Information for Ionizing radiation modulates the TRAIL death-inducing signaling complex, allowing bypass of the mitochondrial apoptosis pathway.

AFFILIATION: Division of Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Country: England

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MEDLINETA: Oncogene

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