title: A novel TXNIP-based mechanism for Cx43-mediated regulation of oxidative drug injury.
abstract: Gap junctions (GJs) play an important role in the regulation of cell response to many drugs. However, little is known about their mechanisms. Using an in vitro model of cytotoxicity induced by geneticin (G418), we explored the potential signalling mechanisms involved. Incubation of cells with G418 resulted in cell death, as indicated by the change in cell morphology, loss of cell viability and activation of caspase-3. Before the onset of cell injury, G418 induced reactive oxygen species (ROS) generation, activated oxidative sensitive kinase P38 and caused a shift of connexin 43 (Cx43) from non-phosphorylated form to hyperphosphorylated form. These changes were largely prevented by antioxidants, suggesting an implication of oxidative stress. Downregulation of Cx43 with inhibitors or siRNA suppressed the expression of thioredoxin-interacting protein (TXNIP), activated Akt and protected cells against the toxicity of G418. Further analysis revealed that inhibition of TXNIP with siRNA activated Akt and reproduced the protective effect of Cx43-inhibiting agents, whereas suppression of Akt sensitized cells to the toxicity of G418. Furthermore, interference of TXNIP/Akt also affected puromycin- and adriamycin-induced cell injury. Our study thus characterized TXNIP as a presently unrecognized molecule implicated in the regulatory actions of Cx43 on oxidative drug injury. Targeting Cx43/TXNIP/Akt signalling cascade might be a promising approach to modulate cell response to drugs.
authors.affiliation: Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan.|Department of Nephrology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Gao
authors.affiliation: Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chi
authors.affiliation: Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan.
authors.forename: Xiling
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Urology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan.|Department of Urology, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Nephrology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.affiliation: Department of Urology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Takeda
authors.affiliation: Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan.
authors.forename: Jian
authors.initials: J
authors.lastname: Yao
mesh_terms: D000617:Aminoglycosides / Q000009:adverse effects*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D018031:Connexin 43 / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology; D017629:Gap Junctions / Q000187:drug effects / Q000378:metabolism; D005839:Gentamicins / Q000009:adverse effects; D051379:Mice; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011691:Puromycin / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000617:Aminoglycosides; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D018031:Connexin 43; D005839:Gentamicins; C493796:TXNIP protein, rat; D011691:Puromycin; D004317:Doxorubicin; C010680:antibiotic G 418; D051057:Proto-Oncogene Proteins c-akt
keywords: Akt; TXNIP; connexin 43; cytotoxicity; gap junction; oxidative stress