title: Lifeguard inhibition of Fas-mediated apoptosis: A possible mechanism for explaining the cisplatin resistance of triple-negative breast cancer cells.
abstract: Triple-negative breast cancer does not express estrogen receptor-α, progesterone or the HER2 receptor making hormone or antibody therapy ineffective. Cisplatin may initiate p73-dependent apoptosis in p53 mutant cell lines through Fas trimerization and Caspase-8 activation and Bax up regulation and subsequent Caspase-9 activation. The triple-negative breast cancer, MDA-MB-231, overexpresses the protein Lifeguard, which inhibits Fas-mediated apoptosis by inhibiting Caspase-8 activation after Fas trimerization. The relationship between Fas, Lifeguard and cisplatin is investigated by down regulating Lifeguard via shRNA. Results demonstrate that cisplatin's efficacy increases when Lifeguard is down regulated. Lifeguard Knockdown MDA-MB-231 continue to decrease in cell viability from 24 to 48h after cisplatin treatment while no additional decrease in viability is observed in the Wild-Type MDA over the same period. Higher Caspase-8 activity in the Lifeguard knockdown MDA after cisplatin administration could explain the significant decrease in cell viability from 24 to 48h. This cell type is also more sensitive to Fas ligand-mediated reductions in cell viability, confirming Lifeguard's anti-apoptotic function through the Fas receptor. This research suggests that the efficacy of chemotherapy acting through the Fas pathway would increase if Lifeguard were not overexpressed to inhibit Fas-mediated apoptosis.
authors.affiliation: Department of Biology, College of Arts and Sciences, University of Rochester, Rochester, NY14627, United States. Electronic address: danradin1@gmail.com.
authors.forename: Daniel
authors.initials: D
authors.lastname: Radin
authors.affiliation: Cortex Pharmaceuticals, Glen Rock, NJ 07452, United States.
authors.forename: Arnold
authors.initials: A
authors.lastname: Lippa
authors.affiliation: Biology department, College of Arts and Sciences, New York University, New York NY 10003, United States.
authors.forename: Parth
authors.initials: P
authors.lastname: Patel
authors.affiliation: Bergen County Academies, Hackensack NJ 07601, United States.
authors.forename: Donna
authors.initials: D
authors.lastname: Leonardi
mesh_terms: D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D053181:Caspase 8 / Q000096:biosynthesis; D053453:Caspase 9; D045744:Cell Line, Tumor; D002470:Cell Survival; D002945:Cisplatin / Q000494:pharmacology*; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004797:Enzyme-Linked Immunosorbent Assay; D053222:Fas Ligand Protein / Q000378:metabolism*; D005260:Female; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D064726:Triple Negative Breast Neoplasms / Q000235:genetics*; D019014:fas Receptor / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C400427:FAIM2 protein, human; D053222:Fas Ligand Protein; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D019014:fas Receptor; D019869:Phosphatidylinositol 3-Kinases; D053181:Caspase 8; D053453:Caspase 9; D002945:Cisplatin
keywords: Apoptosis; Caspase-8; Cisplatin; Fas; Lifeguard; Triple-negative breast cancer