title: Antioxidants decrease the apoptotic effect of 5-Fu in colon cancer by regulating Src-dependent caspase-7 phosphorylation.
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.
authors.affiliation: 1] Department of Cellular and Molecular Biology, Hormel Institute, University of Minnesota, 801 16th Avenue N.E., Austin, MN 55912, USA [2] Department of General Surgery, the First Affiliated Hospital of Zhengzhou University, 1 Jianshe Road, Henan 450000, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Fu
authors.affiliation: 1] Department of Cellular and Molecular Biology, Hormel Institute, University of Minnesota, 801 16th Avenue N.E., Austin, MN 55912, USA [2] Department of Physiology and Pathophysiology, Basic Medical School, Zhengzhou University, 100 KeXue Road, Henan 450001, China.
authors.forename: G
authors.initials: G
authors.lastname: Yang
authors.affiliation: Department of Cellular and Molecular Biology, Hormel Institute, University of Minnesota, 801 16th Avenue N.E., Austin, MN 55912, USA.
authors.forename: F
authors.initials: F
authors.lastname: Zhu
authors.affiliation: Department of Cellular and Molecular Biology, Hormel Institute, University of Minnesota, 801 16th Avenue N.E., Austin, MN 55912, USA.
authors.forename: C
authors.initials: C
authors.lastname: Peng
authors.affiliation: Department of Cellular and Molecular Biology, Hormel Institute, University of Minnesota, 801 16th Avenue N.E., Austin, MN 55912, USA.
authors.forename: W
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Cellular and Molecular Biology, Hormel Institute, University of Minnesota, 801 16th Avenue N.E., Austin, MN 55912, USA.
authors.forename: H
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Cellular and Molecular Biology, Hormel Institute, University of Minnesota, 801 16th Avenue N.E., Austin, MN 55912, USA.
authors.forename: H-G
authors.initials: HG
authors.lastname: Kim
authors.affiliation: Department of Cellular and Molecular Biology, Hormel Institute, University of Minnesota, 801 16th Avenue N.E., Austin, MN 55912, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Bode
authors.affiliation: Department of Physiology and Pathophysiology, Basic Medical School, Zhengzhou University, 100 KeXue Road, Henan 450001, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Dong
authors.affiliation: Department of Cellular and Molecular Biology, Hormel Institute, University of Minnesota, 801 16th Avenue N.E., Austin, MN 55912, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Dong
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants; D017209:Apoptosis / Q000187:drug effects; D053179:Caspase 7 / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D000075202:Contraindications; D004347:Drug Interactions; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D016392:Proto-Oncogene Proteins pp60(c-src); D053179:Caspase 7; D005472:Fluorouracil