title: Simvastatin-induced up-regulation of gap junctions composed of connexin 43 sensitize Leydig tumor cells to etoposide: an involvement of PKC pathway.
abstract: Some of lipophilic statins have been reported to enhance toxicities induced by antineoplastic agents but the underling mechanism is unclear. The authors investigated the involvement of Cx43-mediated gap junction intercellular communication (GJIC) in the effect of simvastatin on the cellular toxicity induced by etoposide in this study. The results showed that a major component of the cytotoxicity of therapeutic levels of etoposide is mediated by gap junctions composed of connexin 43(Cx43) and simvastatin at the dosage which does not induce cytotoxicity enhances etoposide toxicity by increasing gap junction coupling. The augmentative effect of simvastatin on GJIC was related to the inhibition of PKC-mediated Cx43 phosphorylation at ser368 and subsequent enhancement of Cx43 membrane location induced by the agent. The present study suggests the possibility that upregulation of gap junctions may be utilized to increase the efficacy of anticancer chemotherapies.
authors: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, People's Republic of China; Department of Anesthesia, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, People's Republic of China.
authors: Lingzhi
authors: L
authors: Wang
authors: Yanni
authors: Y
authors: Fu
authors: Jianxin
authors: J
authors: Peng
authors: Dengpan
authors: D
authors: Wu
authors: Meiling
authors: M
authors: Yu
authors: Chengfang
authors: C
authors: Xu
authors: Qin
authors: Q
authors: Wang
authors: Liang
authors: L
authors: Tao
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002450:Cell Communication / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018031:Connexin 43 / Q000032:analysis* / Q000378:metabolism; D005047:Etoposide / Q000494:pharmacology*; D017629:Gap Junctions / Q000737:chemistry / Q000187:drug effects*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007984:Leydig Cell Tumor / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D011493:Protein Kinase C / Q000502:physiology*; D019821:Simvastatin / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D018031:Connexin 43; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D005047:Etoposide; D019821:Simvastatin; D011493:Protein Kinase C
keywords: 12-O-tetradecanoylphorbol 13-acetate; 3-(N-[dimethylamino]propyl-3-indolyl)-4-(3-indolyl)maleimide; Connexin 43; Etoposide; GF109203X; GJIC; Gap junction; MLTC; PKC; Simvastatin; TPA; gap junctional intercellular communication; murine Leydig tumor cell