Ionizing radiation can overcome resistance to TRAIL in TRAIL-resistant cancer cells

Although the majority of cancer cells are killed by TRAIL (tumor necrosis f actor-related apoptosis-inducing ligand treatment), certain types show resi stance to it. Ionizing radiation also induces cell death in cancer cells an d may share common intracellular pathways with TRAIL leading to apoptosis. In the present study, we examined whether ionizing radiation could overcome TRAIL resistance in the variant Jurkat clones. We first selected TRAIL-res istant or -sensitive Jurkat clones and examined cross-responsiveness of the clones between TRAIL and radiation. Treatment with gamma -radiation induce d significant apoptosis in all the clones, indicating that there seemed to be no cross-resistance between TRAIL and radiation. Combined treatment of r adiation with TRAIL synergistically enhanced killing of TRAIL-resistant cel ls, compared to TRAIL or radiation alone. Apoptosis induced by combined tre atment of TRAIL. and radiation in TRAIL-resistant cells was associated with cleavage of caspase-8 and the proapoptotic Bid protein, resulting in the a ctivation of caspase-9 and caspase-3. No changes in the expressions of TRAI L receptors (DR4 and DR5) and Bcl-2 or Bax were found after treatment. The caspase inhibitor z-VAD-fmk completely counteracted the synergistic cell ki lling induced by combined treatment of TRAIL and gamma -radiation. These re sults demonstrated that ionizing radiation in combination with TRAIL could overcome resistance to TRAIL in TRAIL-resistant cells through TRAIL recepto r-independent synergistic activation of the cascades of the caspase-8 pathw ay, suggesting a potential clinical application of combination treatment of TRAIL and ionizing radiation to TRAIL-resistant cancer cells. (C) 2001 Pub lished by Elsevier Science B.V. on behalf of the Federation of European Bio chemical Societies.