14-3-3σ regulation by p53 mediates a chemotherapy response to 5-fluorouracil in MCF-7 breast cancer cells via Akt inactivation

FEBS Lett. 2012 Jan 20;586(2):163-8. doi: 10.1016/j.febslet.2011.11.034. Epub 2011 Dec 16.

Abstract

We previously demonstrated that 14-3-3σ was downregulated in 5-fluorouracil (5-Fu)-resistant MCF-7 breast cancer cells (MCF-7/5-Fu). Here, we found that stably enhanced 14-3-3σ expression strengthened the effects of 5-Fu, Mitoxantrone and cDDP. 14-3-3σ stabilised the p53 protein and bound Akt to inhibit its activity and its downstream targets: survivin, Bcl-2 and NF-κB-p50. In addition, decreased p53 expression, but not promoter hypermethylation, was responsible for the downregulation of 14-3-3σ in MCF-7/5-Fu cells. Meanwhile, initial treatments with high concentrations of 5-Fu clearly induced 14-3-3σ and p53 expression in a time-dependent manner. 14-3-3σ-mediated molecular events that synergise with p53 may play important roles in the chemotherapy of breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 14-3-3 Proteins / genetics*
  • 14-3-3 Proteins / metabolism
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Biomarkers, Pharmacological / metabolism
  • Biomarkers, Tumor / genetics*
  • Biomarkers, Tumor / metabolism
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Carcinoma / drug therapy
  • Carcinoma / genetics
  • Carcinoma / metabolism
  • Carcinoma / pathology*
  • Cell Line, Tumor
  • Down-Regulation / drug effects
  • Drug Evaluation, Preclinical
  • Enzyme Activation / drug effects
  • Exonucleases / genetics*
  • Exonucleases / metabolism
  • Exoribonucleases
  • Female
  • Fluorouracil / administration & dosage
  • Fluorouracil / pharmacology*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Oncogene Protein v-akt / antagonists & inhibitors*
  • Oncogene Protein v-akt / metabolism
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor Protein p53 / physiology*

Substances

  • 14-3-3 Proteins
  • Biomarkers, Pharmacological
  • Biomarkers, Tumor
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Oncogene Protein v-akt
  • Exonucleases
  • Exoribonucleases
  • SFN protein, human
  • Fluorouracil