Open AccessA novel TXNIP ‐based mechanism for Cx43‐mediated regulation of oxidative drug injury
Author(s) -
Gao Kun,
Chi Yuan,
Zhang Xiling,
Zhang Hui,
Li Gang,
Sun Wei,
Takeda Masayuki,
Yao Jian
Publication year - 2015
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.12641
Subject(s) - txnip , oxidative stress , protein kinase b , microbiology and biotechnology , viability assay , pi3k/akt/mtor pathway , chemistry , biology , signal transduction , cell , biochemistry , thioredoxin
Gap junctions ( GJ s) 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 si RNA 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 si RNA 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.