title: Redistribution of DR4 and DR5 in lipid rafts accounts for the sensitivity to TRAIL in NSCLC cells.
abstract: The selective toxicity of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) against tumor cells makes it a potential targeted drug for treating non-small cell lung carcinomas (NSCLC). However, the majority of established human NSCLC cell lines are either partially or completely resistant to TRAIL, resulting in the limitation for clinical use of rhTRAIL and its agonistic antibodies. In this study, compared to TRAIL-sensitive H460 cell line, TRAIL-resistant A549 cell line showed a similar expression level of DR5 and a higer expression level of DR4. It indicates that there is no positive correlation between the expression levels of death receptors and sensitivity to TRAIL. However, tests on A549 cells with DR4 siRNA transfection revealed that DR4-competitive binding to TRAIL could not affect the capacity of TRAIL in inducing apoptosis. Instead, further studies found that the aggregation of DR4 and DR5 in lipid rafts only occured in H460 cells with TRAIL pretreatment. It suggested that the TRAIL-induced redistribution of DR4 and DR5 in lipid rafts contributed to the sensitivity to TRAIL in TRAIL-sensitive NSCLC H460 cell line, which was also confirmed by intervention tests of the cholesterol-sequestering agent nystatin.
authors.affiliation: Department of Radiation and Medical Oncology, Zhongnan Hospital, Wuhan University, 169 Donghu Road, Wuchang District, Wuhan 430071, P.R. China.
authors.forename: Wen
authors.initials: W
authors.lastname: Ouyang
authors.forename: Chunxu
authors.initials: C
authors.lastname: Yang
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.forename: Jie
authors.initials: J
authors.lastname: Xiong
authors.forename: Junhong
authors.initials: J
authors.lastname: Zhang
authors.forename: Yahua
authors.initials: Y
authors.lastname: Zhong
authors.forename: Gong
authors.initials: G
authors.lastname: Zhang
authors.forename: Fuxiang
authors.initials: F
authors.lastname: Zhou
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Zhou
authors.forename: Conghua
authors.initials: C
authors.lastname: Xie
mesh_terms: D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D020868:Gene Silencing; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism*; D021962:Membrane Microdomains / Q000378:metabolism*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000633:toxicity*
chemical_list: D000970:Antineoplastic Agents; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand