title: Activation of β-catenin by inhibitors of glycogen synthase kinase-3 ameliorates cisplatin-induced cytotoxicity and pro-inflammatory cytokine expression in HEI-OC1 cells.
abstract: Cisplatin is used in the treatment of a wide variety of solid tumors, but its use is limited by its serious adverse effects, including ototoxicity. Glycogen synthase kinase-3 (GSK-3) is a ubiquitously expressed serine/threonine kinase that regulates a variety of cellular functions by phosphorylating its substrates. However, the otoprotective effect of GSK-3 inhibitors is poorly understood. Here, we investigated whether GSK-3 is involved in cisplatin-induced ototoxicity in HEI-OC1 cells and organs of Corti (OCs). GSK-3 inhibitors suppressed cisplatin-induced apoptosis determined by decreased p53 activity, and also decreased expression of PARP and p53 target genes such as p21 and PUMA. The effect of GSK-3 inhibitors was mediated by markedly increased nuclear β-catenin that in turn blocked nuclear translocation of NF-κB. siRNA-mediated β-catenin knockdown markedly increased the expression of NF-κB target genes, such as TNF-α and IL-6. Our data suggest that the GSK-3/β-catenin pathway may play a central role in cisplatin-mediated cytotoxicity in HEI-OC1 cells and hair cells of OCs in vitro.
authors.affiliation: Center for Metabolic Function Regulation and Department of Microbiology, School of Medicine, Wonkwang University, Iksan, South Korea.
authors.forename: Se-Jin
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Center for Metabolic Function Regulation and Department of Microbiology, School of Medicine, Wonkwang University, Iksan, South Korea.
authors.forename: Jae-Young
authors.initials: JY
authors.lastname: Lim
authors.affiliation: Center for Metabolic Function Regulation and Department of Microbiology, School of Medicine, Wonkwang University, Iksan, South Korea.
authors.forename: Joon No
authors.initials: JN
authors.lastname: Lee
authors.affiliation: Center for Metabolic Function Regulation and Department of Microbiology, School of Medicine, Wonkwang University, Iksan, South Korea.
authors.forename: Seong-Kyu
authors.initials: SK
authors.lastname: Choe
authors.affiliation: Center for Metabolic Function Regulation and Department of Microbiology, School of Medicine, Wonkwang University, Iksan, South Korea.
authors.forename: Yong-Il
authors.initials: YI
authors.lastname: Kim
authors.affiliation: Center for Metabolic Function Regulation and Department of Microbiology, School of Medicine, Wonkwang University, Iksan, South Korea.
authors.forename: Seung Ryel
authors.initials: SR
authors.lastname: Song
authors.affiliation: Department of Internal Medicine, Gunsan Medical Center, Gunsan, South Korea.
authors.forename: Meyoung
authors.initials: M
authors.lastname: Cho
authors.affiliation: Center for Metabolic Function Regulation and Department of Microbiology, School of Medicine, Wonkwang University, Iksan, South Korea.
authors.forename: Hong-Seob
authors.initials: HS
authors.lastname: So
authors.affiliation: Center for Metabolic Function Regulation and Department of Microbiology, School of Medicine, Wonkwang University, Iksan, South Korea. Electronic address: rkpark@wku.ac.kr.
authors.forename: Raekil
authors.initials: R
authors.lastname: Park
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D002945:Cisplatin / Q000633:toxicity*; D016207:Cytokines / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics; D051379:Mice; D016328:NF-kappa B / Q000235:genetics; D009925:Organ of Corti / Q000187:drug effects / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D015850:Interleukin-6; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D051176:beta Catenin; D038362:Glycogen Synthase Kinase 3; D002945:Cisplatin
keywords: Auditory cells; Cisplatin; Glycogen synthase kinase-3 (GSK-3); Ototoxicity; Pro-inflammatory cytokines; Wnt/β-catenin