Antioxidants decrease the apoptotic effect of 5-Fu in colon cancer by regulating Src-dependent caspase-7 phosphorylation View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2014-01-09

AUTHORS

Y Fu, G Yang, F Zhu, C Peng, W Li, H Li, H-G Kim, A M Bode, Z Dong, Z Dong

ABSTRACT

Although the rate of development of drug resistance remains very high, 5-fluorouracil (5-Fu) is still the most common chemotherapeutic drug used for the treatment of colon cancer. A better understanding of the mechanism of why cancers develop resistance to 5-Fu could improve its therapeutic effect. Sometimes, antioxidants are used simultaneously with 5-Fu treatment. However, a recent clinical trial showed no advantage or even a harmful effect of combining antioxidants with 5-Fu compared with administration of 5-Fu alone. The mechanism explaining this phenomenon is still poorly understood. In this study, we show that 5-Fu can induce reactive oxygen species-dependent Src activation in colon cancer cells. Mouse embryonic fibroblasts that are deficient in Src showed a clear resistance to 5-Fu, and knocking down Src protein expression in colon cancer cells also decreased 5-Fu-induced apoptosis. We found that Src could interact with and phosphorylate caspase-7 at multiple tyrosine sites. Functionally, the tyrosine phosphorylation of caspase-7 increases its activity, thereby enhancing cellular apoptosis. When using 5-Fu and antioxidants together, Src activation was blocked, resulting in decreased 5-Fu-induced apoptosis. Our results provide a novel explanation as to why 5-Fu is not effective in combination with some antioxidants in colon cancer patients, which is important for clinical chemotherapy. More... »

PAGES

e983-e983

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/cddis.2013.509

DOI

http://dx.doi.org/10.1038/cddis.2013.509

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1017516403

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/24407236


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