title: TRAIL-activated EGFR by Cbl-b-regulated EGFR redistribution in lipid rafts antagonises TRAIL-induced apoptosis in gastric cancer cells.
abstract: Most gastric cancer cells are resistant to tumour necrosis factor-related apoptosis-inducing ligand (TRAIL). Since TRAIL resistance is associated with lipid rafts, in which both death receptors and epidermal growth factor receptors (EGFR) are enriched, our aim is to identify how lipid raft-regulated receptor redistribution influences the sensitivity of TRAIL in gastric cancer cells. In TRAIL-resistant gastric cancer cells, TRAIL did not induce effective death-inducing signalling complex (DISC) formation in lipid rafts, accompanied with EGFR translocation into lipid rafts, and activation of EGFR pathway. Knockdown of casitas B-lineage lymphoma-b (Cbl-b) enhanced TRAIL-induced apoptosis by promoting DISC formation in lipid rafts. However, knockdown of Cbl-b also enhanced EGFR translocation into lipid rafts and EGFR pathway activation induced by TRAIL. Either using inhibitors of EGFR or depletion of EGFR with small interfering RNA (siRNA) prevented EGFR pathway activation, and thus increased TRAIL-induced apoptosis, especially in Cbl-b knockdown clones. Taken together, TRAIL-induced EGFR activation through Cbl-b-regulated EGFR redistribution in lipid rafts antagonised TRAIL-induced apoptosis. The contribution of DISC formation and the inhibition of EGFR signal triggered in lipid rafts are both essential for increasing the sensitivity of gastric cancer cells to TRAIL.
authors.affiliation: Department of Medical Oncology, The First Hospital of China Medical University, Shenyang 110001, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Xu
authors.forename: Ye
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.forename: Jinglei
authors.initials: J
authors.lastname: Qu
authors.forename: Xuejun
authors.initials: X
authors.lastname: Hu
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.forename: Huachuan
authors.initials: H
authors.lastname: Zheng
authors.forename: Xiujuan
authors.initials: X
authors.lastname: Qu
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Liu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000502:physiology; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D021962:Membrane Microdomains / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D050721:Proto-Oncogene Proteins c-cbl / Q000502:physiology*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D053418:Death Domain Receptor Signaling Adaptor Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C492211:CBLB protein, human; D050721:Proto-Oncogene Proteins c-cbl; D066246:ErbB Receptors