title: Trichostatin A reduces cisplatin-induced ototoxicity through the STAT6 signaling pathway.
abstract: Cisplatin-induced ototoxicity limits its wide application in the treatment of cancer. A number of pro-inflammatory factors have been shown to be involved in cisplatin-induced ototoxicity. Trichostatin A (TSA) is an anti-inflammatory agent that has been shown to exert protective effects against cisplatin-induced ototoxicity. In the present study, we hypothesized that TSA may protect cochlear hair cells from cisplatin-induced damage by regulating the interleukin (IL)-4/signal transducer and activator of transcription (STAT)6 signaling pathway. Wistar rat cochlear explants were cultured in DMEM. The differentially expressed genes of the basilar membrane were identified by microarray analysis of global expression profiles. Hair cells were stained with rhodamine phalloidin and observed under a scanning electron microscope to evaluate the protective effects of TSA against cisplatin-induced cochlear hair cell damage. The levels of cytokines in the supernatant of the cultured basilar membranes was measured using ELISA. STAT6 and phosphorylated (p-)STAT6 expression was measured by western blot analysis. Morphological observation revealed that cisplatin induced the disarrangement of the cochlear hair cells, as well as the fusion and detachment of the cilia, while these aberrant alterations were inhibited by TSA, suggesting that TSA exerts a protective effect against cisplatin-induced damage to hair cells. Furthermore, the increase in the expression of STAT6 and p-STAT6 induced by cisplatin was reversed by treatment with TSA, accompanied by the decreased expression of IL-1β, IL-4 and IL-6. Therefore, our data demonstrate that TSA reduces cisplatin-induced ototoxicity by inhibiting pro-inflammatory factor-mediated STAT6 signaling. Thus, TSA may be used to prevent the side-effects associated with the use of cisplatin in cancer treatment.
authors.affiliation: Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, P.R. China.
authors.forename: Ji
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, The First Hospital of Jilin University, Changchun, Jilin, P.R. China.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, P.R. China.
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Physiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, P.R. China.
authors.forename: Jingyan
authors.initials: J
authors.lastname: Ge
authors.affiliation: Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, P.R. China.
authors.forename: Jiaqi
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, P.R. China.
authors.forename: Xia
authors.initials: X
authors.lastname: Chen
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002945:Cisplatin / Q000633:toxicity*; D006198:Hair Cells, Auditory / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D006877:Hydroxamic Acids / Q000494:pharmacology*; D015847:Interleukin-4 / Q000276:immunology; D020011:Protective Agents / Q000494:pharmacology; D017208:Rats, Wistar; D050800:STAT6 Transcription Factor / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D006877:Hydroxamic Acids; D020011:Protective Agents; D050800:STAT6 Transcription Factor; D015847:Interleukin-4; C012589:trichostatin A; D002945:Cisplatin