title: Cetuximab enhances TRAIL-induced gastric cancer cell apoptosis by promoting DISC formation in lipid rafts.
abstract: TRAIL is a member of the tumor necrosis factor family that selectively induces cancer cell apoptosis. However, gastric cancer cells are insensitive to TRAIL. Our and others studies showed that the inhibition of EGFR pathway activation could increase the sensitivity of TRAIL in cancer cells. But the detailed mechanism is not fully understood. In the present study, compared with TRAIL or cetuximab (an anti-EGFR monoclonal antibody) alone, treatment with the TRAIL/cetuximab combination significantly promoted death receptor 4 (DR4) clustering as well as the translocation of both DR4 and Fas-associated death domain-containing protein (FADD) into lipid rafts. This in turn resulted in caspase-8 cleavage and the formation of the death-inducing signaling complex (DISC) in these lipid rafts. Cholesterol-depletion with methyl-β-cyclodextrin partially prevented DR4 clustering and DISC formation, and thus partially reversed apoptosis induced by the TRAIL/cetuximab dual treatment. These results indicate that cetuximab increases TRAIL-induced gastric cancer cell apoptosis at least partially through the promotion of DISC formation in lipid rafts.
authors: Department of Medical Oncology, The First Hospital of China Medical University, Shenyang 110001, China.
authors: Ling
authors: L
authors: Xu
authors: Xuejun
authors: X
authors: Hu
authors: Xiujuan
authors: X
authors: Qu
authors: Kezuo
authors: K
authors: Hou
authors: Huachuan
authors: H
authors: Zheng
authors: Yunpeng
authors: Y
authors: Liu
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D000068818:Cetuximab; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000378:metabolism*; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005753:Gastric Mucosa / Q000378:metabolism; D006801:Humans; D021962:Membrane Microdomains / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D021381:Protein Transport / Q000187:drug effects; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013270:Stomach / Q000187:drug effects* / Q000473:pathology; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D053418:Death Domain Receptor Signaling Adaptor Proteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; D066246:ErbB Receptors; D000068818:Cetuximab
keywords: Cetuximab; DISC; Gastric cancer; Lipid rafts; TRAIL