Induction of p53 expression and apoptosis by a recombinant dual-target MDM2/MDMX inhibitory protein in wild-type p53 breast cancer cells

The tumor suppressor gene p53 is often inactivated in breast cancer cells due to gene mutation or overexpression of its repressors (such as murine double minute 2 and murine double minute X). Inhibitors of murine double minute 2 (MDM2) and murine double minute X (MDMX) could lead to tumor suppression by restoration of p53 activity and such an approach is a promising strategy for future control of breast cancer. This study aimed to investigate the feasibility of the recombinant MDM2 and MDMX inhibitory protein in control of breast cancer in vitro. A cell-permeable dual-target MDM2/MDMX inhibitory protein was expressed in E. coli and incubated with p53 wild-type breast cancer cells. The data showed that this recombinant MDM2/MDMX inhibitory protein reduced the viability of MCF-7 and ZR-75-30 breast cancer cell lines and promoted cell cycle arrest and apoptosis by activation and stabilization of the p53 protein. Mechanistically, this MDM2/MDMX inhibitory protein increased the expression of p21, Bax and puma proteins, and inhibitory expression of MDM2 and MDMX proteins. This recombinant protein showed a better in vitro effect than that of nutlin-3, a small molecule MDM2 inhibitor. The data further support the hypothesis that targeting of the p53 gene pathway could effectively control breast cancer.