Journal of Cellular and Molecular Medicine | |
A novel TXNIP‐based mechanism for Cx43‐mediated regulation of oxidative drug injury | |
Kun Gao1  Yuan Chi1  Xiling Zhang1  Hui Zhang1  Gang Li2  Wei Sun3  Masayuki Takeda2  | |
[1] Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan;Department of Urology, 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 | |
关键词: connexin 43; gap junction; oxidative stress; cytotoxicity; TXNIP; Akt; | |
DOI : 10.1111/jcmm.12641 | |
来源: Wiley | |
【 摘 要 】
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.Abstract
【 授权许可】
CC BY
© 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
【 预 览 】
Files | Size | Format | View |
---|---|---|---|
RO202107150013767ZK.pdf | 931KB | download |