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

Y. Fu, G. Yang, F. Zhu, C. Peng, W. Li, H. Li, HONGGYUM KIM, A. M. Bode, Zigang Dong

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

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.

Original languageEnglish (US)
Article numbere983
JournalCell Death and Disease
Volume5
Issue number1
DOIs
StatePublished - Jan 1 2014

Keywords

  • 5-Fu
  • Antioxidant
  • Apoptosis
  • Caspase-7
  • Colon cancer
  • Src

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