title: Proteasome inhibitors induce auditory hair cell death through peroxisome dysfunction.
abstract: Even though bortezomib, a proteasome inhibitor, is a powerful chemotherapeutic agent used to treat multiple myeloma (MM) and other lymphoma cells, recent clinical reports suggest that the proteasome inhibitor therapy may be associated with severe bilateral hearing loss. We herein investigated the adverse effect of proteasome inhibitor on auditory hair cells. Treatment of a proteasome inhibitor destroys stereocilia bundles of hair cells resulting in the disarray of stereocilia in the organ of Corti explants. Since proteasome activity may be potentially important for biogenesis and function of the peroxisome, we tested whether proteasome activity is necessary for maintaining functional peroxisomes. Our results showed that treatment of a proteasome inhibitor significantly decreases both the number of peroxisomes and expression of peroxisomal proteins such as PMP70 and Catalase. In addition, we also found that proteasome inhibitor impairs the import pathway of PTS1-peroxisome matrix proteins. Taken together, our findings support recent clinical reports of hearing loss associated with proteasome inhibition. Mechanistically, peroxisome dysfunction may contribute to hair cell damage and hearing loss in response to the treatment of a proteasome inhibitor.
authors.affiliation: Center for Metabolic Function Regulation, Department of Microbiology, Wonkwang University School of Medicine, Iksan, South Korea.
authors.forename: Joon No
authors.initials: JN
authors.lastname: Lee
authors.affiliation: Center for Metabolic Function Regulation, Department of Microbiology, Wonkwang University School of Medicine, Iksan, South Korea.
authors.forename: Seul-Gi
authors.initials: SG
authors.lastname: Kim
authors.affiliation: Center for Metabolic Function Regulation, Department of Microbiology, Wonkwang University School of Medicine, Iksan, South Korea.
authors.forename: Jae-Young
authors.initials: JY
authors.lastname: Lim
authors.affiliation: Center for Metabolic Function Regulation, Department of Microbiology, Wonkwang University School of Medicine, Iksan, South Korea.
authors.forename: Se-Jin
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Center for Metabolic Function Regulation, Department of Microbiology, Wonkwang University School of Medicine, Iksan, South Korea.
authors.forename: Seong-Kyu
authors.initials: SK
authors.lastname: Choe
authors.affiliation: Center for Metabolic Function Regulation, Department of Microbiology, Wonkwang University School of Medicine, Iksan, South Korea. Electronic address: rkpark@wku.ac.kr.
authors.forename: Raekil
authors.initials: R
authors.lastname: Park
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects; D001897:Boronic Acids / Q000009:adverse effects; D000069286:Bortezomib; D002374:Catalase / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival; D006198:Hair Cells, Auditory / Q000187:drug effects*; D034381:Hearing Loss / Q000139:chemically induced* / Q000378:metabolism*; D006801:Humans; D008055:Lipids / Q000737:chemistry; D009925:Organ of Corti / Q000187:drug effects; D020675:Peroxisomes / Q000378:metabolism*; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000009:adverse effects*; D011719:Pyrazines / Q000009:adverse effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species
chemical_list: C063305:ABCD3 protein, human; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D001897:Boronic Acids; D008055:Lipids; D061988:Proteasome Inhibitors; D011719:Pyrazines; D017382:Reactive Oxygen Species; D000069286:Bortezomib; D002374:Catalase; D046988:Proteasome Endopeptidase Complex
keywords: Auditory hair cell; Hearing loss; Peroxisome dysfunction; Proteasome inhibitor