title: Formation of the IGF1R/CAV1/SRC tri-complex antagonizes TRAIL-induced apoptosis in gastric cancer cells.
abstract: Lipid rafts provide a biological platform for apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). We previously reported that insulin-like growth factor 1 receptor (IGF1R) translocation into lipid rafts helped to explain TRAIL resistance. However, it was not clear whether TRAIL resistance was caused by the interaction of IGF1R with caveolin-1 (CAV1) and the non-receptor tyrosine kinase SRC in lipid rafts of gastric cancer cells. Here, we observed high IGF1R expression in TRAIL-resistant gastric cancer cells, and showed that IGF1R combined with both CAV1 and SRC in a native complex. TRAIL was shown to promote the formation of the IGF1R/CAV1/SRC tri-complex and the activation of these three molecules. Knockdown of IGF1R or CAV1 or inhibition of SRC activity reduced the formation of this tri-complex and enhanced TRAIL-induced apoptosis. Furthermore, the overexpression of microRNA-194 reversed TRAIL resistance by reducing IGF1R expression. In summary, TRAIL increased formation of the IGF1R/CAV1/SRC tri-complex and the activation of downstream survival pathways, leading to TRAIL resistance in gastric cancer cells.
authors.affiliation: Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, 110001, China.|Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, 110001, China.
authors.forename: Tianshu
authors.initials: T
authors.lastname: Guo
authors.affiliation: Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, 110001, China.|Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, 110001, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, 110001, China.|Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, 110001, China.
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Che
authors.affiliation: Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, 110001, China.|Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, 110001, China.
authors.forename: Simeng
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, 110001, China.|Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, 110001, China.
authors.forename: Ce
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, 110001, China.|Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, 110001, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, 110001, China.|Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, 110001, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Gong
authors.affiliation: Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, 110001, China.|Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, 110001, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Ma
authors.affiliation: Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, 110001, China.|Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, 110001, China.
authors.forename: Yibo
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, 110001, China.|Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, 110001, China.
authors.forename: Kezuo
authors.initials: K
authors.lastname: Hou
authors.affiliation: Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, 110001, China.|Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, 110001, China.
authors.forename: Huiming
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Respiratory Medicine, the First Hospital of China Medical University, Shenyang, 110001, China.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, 110001, China.|Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, 110001, China.
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, 110001, China.|Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, 110001, China.
authors.forename: Xiujuan
authors.initials: X
authors.lastname: Qu
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D051242:Caveolin 1 / Q000378:metabolism*; D045744:Cell Line, Tumor; D006801:Humans; D021962:Membrane Microdomains / Q000378:metabolism; D035683:MicroRNAs / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D017451:Receptors, Somatomedin / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: C495540:CAV1 protein, human; D051242:Caveolin 1; C000597236:IGF1R protein, human; C554846:MIRN194 microRNA, human; D035683:MicroRNAs; D017451:Receptors, Somatomedin; D053221:TNF-Related Apoptosis-Inducing Ligand; D058539:Phosphatidylinositol 3-Kinase; D017526:Receptor, IGF Type 1; D019061:src-Family Kinases; D048052:Mitogen-Activated Protein Kinase 3
keywords: CAV1; IGF1R; SRC; TRAIL; gastric cancer