論文

査読有り 国際誌
2015年10月

A novel TXNIP-based mechanism for Cx43-mediated regulation of oxidative drug injury.

Journal of cellular and molecular medicine
  • Kun Gao
  • ,
  • Yuan Chi
  • ,
  • Xiling Zhang
  • ,
  • Hui Zhang
  • ,
  • Gang Li
  • ,
  • Wei Sun
  • ,
  • Masayuki Takeda
  • ,
  • Jian Yao

19
10
開始ページ
2469
終了ページ
80
記述言語
英語
掲載種別
DOI
10.1111/jcmm.12641

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.

リンク情報
DOI
https://doi.org/10.1111/jcmm.12641
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/26154105
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4594688
ID情報
  • DOI : 10.1111/jcmm.12641
  • PubMed ID : 26154105
  • PubMed Central 記事ID : PMC4594688

エクスポート
BibTeX RIS