title: Simvastatin protects Sertoli cells against cisplatin cytotoxicity through enhanced gap junction intercellular communication.
abstract: Cisplatin, an important chemotherapeutic agent against testicular germ cell cancer, induces testicular toxicity on Leydig and Sertoli cells, leading to serious side-effects such as azoospermia and infertility. In a previous study, it was found that simvastatin enhanced the sensitivity of Leydig tumor cells to chemotherapeutic toxicity through the enhancement of gap junction functions. In the present study, the effect of simvastatin on the sensitivity of normal Sertoli cells to cisplatin and the role of gap junctions in such effects was investigated. The results showed that, simvastatin attenuated cisplatin toxicity only when cells exhibited high-density culture where gap junctional formation was possible. When gap junction function was decreased by the gap junction inhibitor or by siRNA targeting connexin 43, the protective effect of simvastatin to cisplatin toxicity was substantially attenuated. Simvastatin also enhanced gap junction functions between Sertoli cells. This effect was mediated by the reduction of PKC-mediated connexin phosphorylation, thereby increasing connexin 43 membrane localization. Thus, simvastatin-induced enhancement of gap junction‑mediated intercellular communication attenuated cisplatin toxicity on Sertoli cells. This result indicated that enhancement of gap junction function by simvastatin may have bilateral beneficial effects on cisplatin‑based chemotherapy, enhancing cisplatin killing on cancer while ameliorating the reproduction toxicity.
authors.affiliation: Department of Anaesthesia, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, P.R. China.
authors.forename: Lingzhi
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Hepatobiliary Surgery, Guangdong Province Traditional Chinese Medical Hospital, Guangzhou 510120, P.R. China.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Peng
authors.affiliation: Department of Anaesthesia, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, P.R. China.
authors.forename: Huansen
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, P.R. China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, The First Affiliated Hospital, Bengbu Medical College, Bengbu, Anhui 233004, P.R. China.
authors.forename: Meiling
authors.initials: M
authors.lastname: Yu
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, P.R. China.
authors.forename: Liang
authors.initials: L
authors.lastname: Tao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002450:Cell Communication / Q000187:drug effects; D002460:Cell Line; D002945:Cisplatin / Q000633:toxicity*; D018031:Connexin 43 / Q000378:metabolism; D017629:Gap Junctions / Q000187:drug effects*; D008297:Male; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism; D012708:Sertoli Cells / Q000187:drug effects* / Q000502:physiology; D019821:Simvastatin / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D018031:Connexin 43; C543076:GJA1 protein, mouse; D019821:Simvastatin; D011493:Protein Kinase C; D002945:Cisplatin