title: A mechanism of resistance to TRAIL/Apo2L-induced apoptosis of newly established glioma cell line and sensitisation to TRAIL by genotoxic agents.
abstract: Most tumour cells are sensitive to TRAIL-induced apoptosis, but not normal cells; thus, cancer therapy using TRAIL is expected clinically. Several tumour cells are resistant to TRAIL-induced apoptosis, and various mechanisms of such resistance were reported in individual cases. In this study, we established a TRAIL-resistant glioma cell line, which completely lacked TRAIL receptors. In addition, this tumour cell line had wild-type p53 tumour-suppressive gene, suggesting new mechanisms for tumour cells to expand and escape from immune surveillance. The present study further explored the mechanisms that determine the sensitivity to TRAIL. We show that genotoxic agents such as cisplatin, doxorubicin and camptothecin, in addition to UV radiation, can induce TRAIL-R2 on the cell surface of TRAIL receptor-negative tumour cells. Newly synthesised TRAIL-R2 is functional, so apoptosis is effectively induced by TRAIL, but it is significantly inhibited by constitutive expression of dominant-negative p53. In addition, apoptosis induced by pretreatment of genotoxic agents and additional stimulation of TRAIL is efficiently inhibited by either antagonistic anti-TRAIL-R2 antibody or pan-caspase inhibitor z-VAD-FMK. Taken together, these findings suggest that resistance to TRAIL by lack of TRAIL receptors on glioma is restored by genotoxic agents, which support the new strategies for tumour killing by TRAIL-bearing cytotoxic cells in combination with genotoxic treatment.
authors.affiliation: Department of Orthopedic Surgery, Yamanashi Medical University, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Arizono
authors.forename: H
authors.initials: H
authors.lastname: Yoshikawa
authors.forename: H
authors.initials: H
authors.lastname: Naganuma
authors.forename: Y
authors.initials: Y
authors.lastname: Hamada
authors.forename: Y
authors.initials: Y
authors.lastname: Nakajima
authors.forename: K
authors.initials: K
authors.lastname: Tasaka
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects; D051017:Apoptosis Regulatory Proteins; D015153:Blotting, Western; D002166:Camptothecin / Q000494:pharmacology; D002470:Cell Survival; D002945:Cisplatin / Q000494:pharmacology; D004273:DNA, Neoplasm / Q000187:drug effects*; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005354:Fibrosarcoma / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D012516:Osteosarcoma / Q000378:metabolism / Q000473:pathology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D051017:Apoptosis Regulatory Proteins; D004273:DNA, Neoplasm; D008562:Membrane Glycoproteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D002945:Cisplatin; D002166:Camptothecin