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

Oncogene. 2008 Jan 24;27(5):574-84. doi: 10.1038/sj.onc.1210696. Epub 2007 Aug 6.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Apoptosis
  • Caspases / metabolism
  • DNA Damage
  • Enzyme Activation
  • Fas-Associated Death Domain Protein / metabolism
  • Humans
  • Jurkat Cells
  • Mitochondria / enzymology
  • Mitochondria / metabolism
  • RNA Interference
  • Radiation, Ionizing*
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism*
  • Signal Transduction
  • TNF-Related Apoptosis-Inducing Ligand / physiology*
  • fas Receptor / immunology


  • Antineoplastic Agents
  • FADD protein, human
  • Fas-Associated Death Domain Protein
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • fas Receptor
  • Caspases