title: Acquired TRAIL resistance in human breast cancer cells are caused by the sustained cFLIP(L) and XIAP protein levels and ERK activation.
abstract: We established TRAIL-resistant MDA-231/TR cells from MDA-231 parent cells to understand the mechanism of TRAIL resistance in breast cancer cells. The selected TRAIL-resistant cells were cross-resistant to TNF-alpha/cycloheximide but remained sensitive to DNA-damage drugs such as oxaliplatin and etoposide. The expression levels of death receptors (DR4 and DR5), FADD, cIAP1, cIAP2, and Bcl-2 family were not changed in TRAIL-treated both cells. Significant down-regulation of XIAP and cFLIP was occurred after TRAIL treatment in MDA-231 cells whereas their levels were sustained in MDA-231/TR cells. TRAIL-mediated activation of ERK and JNK were also observed in parent MDA-231 cells but not in MDA-231/TR cells. However, TRAIL-resistant cells showed constitutive activation state after treatment with TRAIL. Pretreatment with PD98059 or transfection of MKK1-DN (dominant negative) expression vector attenuated TRAIL resistance in MDA-231/TR cells. Our findings provide the evidence that the sustained expression level of cFLIP(L) and XIAP protein and constitutive ERK activation may lead to acquired TRAIL resistance in breast cancer cells.
authors.affiliation: Department of Immunology, School of Medicine, Keimyung University, 194 DongSan-Dong Jung-Gu, Taegu 700-712, Republic of Korea.
authors.forename: Tae-Jin
authors.initials: TJ
authors.lastname: Lee
authors.forename: Jung Tae
authors.initials: JT
authors.lastname: Lee
authors.forename: Jong-Wook
authors.initials: JW
authors.lastname: Park
authors.forename: Taeg Kyu
authors.initials: TK
authors.lastname: Kwon
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism*
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D005419:Flavonoids; D047428:Protein Kinase Inhibitors; D053221:TNF-Related Apoptosis-Inducing Ligand; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D020928:Mitogen-Activated Protein Kinases; D053181:Caspase 8; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one