title: Ionizing radiation can overcome resistance to TRAIL in TRAIL-resistant cancer cells.
abstract: Although the majority of cancer cells are killed by TRAIL (tumor necrosis factor-related apoptosis-inducing ligand treatment), certain types show resistance to it. Ionizing radiation also induces cell death in cancer cells and 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-resistant or -sensitive Jurkat clones and examined cross-responsiveness of the clones between TRAIL and radiation. Treatment with gamma-radiation induced significant apoptosis in all the clones, indicating that there seemed to be no cross-resistance between TRAIL and radiation. Combined treatment of radiation with TRAIL synergistically enhanced killing of TRAIL-resistant cells, compared to TRAIL or radiation alone. Apoptosis induced by combined treatment of TRAIL and radiation in TRAIL-resistant cells was associated with cleavage of caspase-8 and the proapoptotic Bid protein, resulting in the activation of caspase-9 and caspase-3. No changes in the expressions of TRAIL receptors (DR4 and DR5) and Bcl-2 or Bax were found after treatment. The caspase inhibitor z-VAD-fmk completely counteracted the synergistic cell killing induced by combined treatment of TRAIL and gamma-radiation. These results demonstrated that ionizing radiation in combination with TRAIL could overcome resistance to TRAIL in TRAIL-resistant cells through TRAIL receptor-independent synergistic activation of the cascades of the caspase-8 pathway, suggesting a potential clinical application of combination treatment of TRAIL and ionizing radiation to TRAIL-resistant cancer cells.
authors.affiliation: Laboratory of Radiation Effect, Korea Cancer Center Hospital, Seoul, Korea.
authors.forename: M R
authors.initials: MR
authors.lastname: Kim
authors.forename: J Y
authors.initials: JY
authors.lastname: Lee
authors.forename: M T
authors.initials: MT
authors.lastname: Park
authors.forename: Y J
authors.initials: YJ
authors.lastname: Chun
authors.forename: Y J
authors.initials: YJ
authors.lastname: Jang
authors.forename: C M
authors.initials: CM
authors.lastname: Kang
authors.forename: H S
authors.initials: HS
authors.lastname: Kim
authors.forename: C K
authors.initials: CK
authors.lastname: Cho
authors.forename: Y S
authors.initials: YS
authors.lastname: Lee
authors.forename: H Y
authors.initials: HY
authors.lastname: Jeong
authors.forename: S J
authors.initials: SJ
authors.lastname: Lee
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D051017:Apoptosis Regulatory Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins / Q000378:metabolism; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D016923:Cell Death / Q000187:drug effects; D002999:Clone Cells; D019008:Drug Resistance, Neoplasm; D006801:Humans; D019169:Jurkat Cells; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D011839:Radiation, Ionizing; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein
chemical_list: D051017:Apoptosis Regulatory Proteins; C494826:BAX protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases