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

We previously demonstrated that 14-3-3 sigma was downregulated in 5-fluorouracil (5-Fu)-resistant MCF-7 breast cancer cells (MCF-7/5-Fu). Here, we found that stably enhanced 14-3-3 sigma expression strengthened the effects of 5-Fu, Mitoxantrone and cDDP. 14-3-3 sigma stabilised the p53 protein and bound Akt to inhibit its activity and its downstream targets: survivin, Bcl-2 and NF-kappa B-p50. In addition, decreased p53 expression, but not promoter hypermethylation, was responsible for the downregulation of 14-3-3 sigma in MCF-7/5-Fu cells. Meanwhile, initial treatments with high concentrations of 5-Fu clearly induced 14-3-3 sigma and p53 expression in a time-dependent manner. 14-3-3 sigma-mediated molecular events that synergise with p53 may play important roles in the chemotherapy of breast cancer. (C) 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.