title: Prevention of cisplatin-induced ototoxicity by the inhibition of gap junctional intercellular communication in auditory cells.
abstract: Cis-diamminedichloroplatinum (cisplatin) is an effective chemotherapeutic drug for cancer therapy. However, most patients treated with cisplatin are at a high risk of ototoxicity, which causes severe hearing loss. Inspired by the "Good Samaritan effect" or "bystander effect" from gap junction coupling, we investigated the role of gap junctions in cisplatin-induced ototoxicity as a potential therapeutic method. We showed that connexin 43 (Cx43) was highly expressed in House Ear Institute-Organ of Corti 1 (HEI-OC1) cells, mediating cell-cell communication. The viability of HEI-OC1 cells was greatly decreased by cisplatin treatment, and cisplatin-treated HEI-OC1 cells showed lower Cx43 expression compared to that of untreated HEI-OC1 cells. In particular, high accumulation of Cx43 was observed around the nucleus of cisplatin-treated cells, whereas scattered punctuate expression of Cx43 was observed in the cytoplasm and membrane in normal cells, suggesting that cisplatin may interrupt the normal gap junction communication by inhibiting the trafficking of Cx43 to cell membranes in HEI-OC1 cells. Interestingly, we found that the inhibition of gap junction activity reduced cisplatin-induced apoptosis of auditory hair cells. Cx43 siRNA- or 18α-GA-treated HEI-OC1 cells showed higher cell viability compared to control HEI-OC1 cells during cisplatin treatment; this was also supported by fluorescence recovery after photobleaching studies. Inhibition of gap junction activity reduced recovery of calcein acetoxymethyl ester fluorescence compared to control cells. Additionally, analysis of the mechanisms involved demonstrated that highly activate extracellular signal-regulated kinase and protein kinase B, combined with inhibition of gap junctions may promote cell viability during cisplatin treatment.
authors.affiliation: Department of Otolaryngology, Ajou University School of Medicine, San 5 Woncheon-dong, Yeongtong-gu, Suwon, 443-721, Republic of Korea.
authors.forename: Yeon Ju
authors.initials: YJ
authors.lastname: Kim
authors.forename: Jangho
authors.initials: J
authors.lastname: Kim
authors.forename: Chunjie
authors.initials: C
authors.lastname: Tian
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Lim
authors.forename: Young Sun
authors.initials: YS
authors.lastname: Kim
authors.forename: Jong Hoon
authors.initials: JH
authors.lastname: Chung
authors.forename: Yun-Hoon
authors.initials: YH
authors.lastname: Choung
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002450:Cell Communication / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002945:Cisplatin / Q000633:toxicity*; D018031:Connexin 43 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D017629:Gap Junctions / Q000378:metabolism*; D006034:Glycyrrhetinic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D006198:Hair Cells, Auditory / Q000166:cytology / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats
chemical_list: D000970:Antineoplastic Agents; D018031:Connexin 43; D034741:RNA, Small Interfering; C119129:18alpha-glycyrrhetinic acid; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D006034:Glycyrrhetinic Acid; D002945:Cisplatin