A mechanism of resistance to TRAIL Apo2L-induced apoptosis of newly established glioma cell line and sensitisation to TRAIL by genotoxic agents

• Published in: British journal of cancer Vol. 88; no. 2; pp. 298 - 306
• Main Authors: ARIZONO, Y, YOSHIKAWA, H, NAGANUMA, H, HAMADA, Y, NAKAJIMA, Y, TASAKA, K
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 27.01.2003
• Subjects: Antineoplastic agents; Antineoplastic Agents - pharmacology; Antineoplastic Agents, Phytogenic - toxicity; Apoptosis - drug effects; Apoptosis - radiation effects; Apoptosis Regulatory Proteins; Biological and medical sciences; Blotting, Western; Camptothecin - pharmacology; Cell Survival; Cisplatin - pharmacology; Combined treatments (chemotherapy of immunotherapy associated with an other treatment); DNA, Neoplasm - drug effects; Doxorubicin - pharmacology; Drug Resistance, Neoplasm; Fibrosarcoma - metabolism; Fibrosarcoma - pathology; Flow Cytometry; Genetics and Genomics; Glioma - drug therapy; Glioma - metabolism; Glioma - pathology; Humans; Medical sciences; Membrane Glycoproteins - pharmacology; Osteosarcoma - metabolism; Osteosarcoma - pathology; Pharmacology. Drug treatments; Receptors, TNF-Related Apoptosis-Inducing Ligand; Receptors, Tumor Necrosis Factor - metabolism; TNF-Related Apoptosis-Inducing Ligand; Transfection; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha - pharmacology; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Antineoplastic agent; p53: genotoxic agents; Doxorubicin; Mechanism; Malignant glioma; Alkaloid; Isomerases; Established cell line; Sensitization; Platinum II Complexes; Human; DNA topoisomerase (ATP-hydrolysing); TRAIL receptors; Nervous system diseases; Drug combination; Treatment resistance; TRAIL; Enzyme; Cytokine; DNA topoisomerase; Enzyme inhibitor; Malignant tumor; In vitro; Biological activity; Cisplatin; Alkylating agent; Ultraviolet radiation; Tumor necrosis factor; Cell death; Central nervous system disease; TNF related apoptosis inducing ligand; Anthracyclins; Apoptosis
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6600666

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.