Genistein induces apoptosis by stabilizing intracellular p53 protein through an APE1-mediated pathway

• Published in: Free radical biology & medicine Vol. 86; pp. 209 - 218
• Main Authors: Zhu, Jianwu, Zhang, Chong, Qing, Yi, Cheng, Yi, Jiang, Xiaolin, Li, Mengxia, Yang, Zhenzhou, Wang, Dong
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-09-2015
• Subjects: Antineoplastic Agents - pharmacology; APE1; Apoptosis; DNA-(Apurinic or Apyrimidinic Site) Lyase - metabolism; Genistein; Genistein - pharmacology; HeLa Cells; Humans; Oxidation-Reduction; Protein Stability; Proteolysis; Signal Transduction; Stability; Tumor Suppressor Protein p53; Wild-type p53; RT; Stability; NSCLC; Wild-type p53; APE1; DMSO; Genistein; GST; Co-IP; DOX; SiRNA; BER; GEN; CHX; ROS; TAC; IPTG; MDM2; TRX; GSH
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2015.05.030

Genistein (GEN) has been previously shown to have a proapoptotic effect on cancer cells through a p53-dependent pathway, the mechanism of which remains unclear. One of its intracellular targets, APE1, protects against apoptosis under genotoxic stress and interacts with p53. In this current study, we explored the mechanism of the proapoptotic effect of GEN by examining the APE1–p53 protein–protein interaction. We initially showed that the p53 protein level was elevated in GEN-treated human non-small lung cancer A549 cells and cervical cancer HeLa cells. By examining both protein synthesis and degradation, we found that GEN enhances p53 intracellular stability by interfering with the interaction of APE1 and p53, which provided a plausible explanation for how GEN initiates apoptosis. Furthermore, we found that the interaction between APE1 and p53 is important for the degradation of p53 and is dependent on the redox domain of APE1 by utilizing the redox domain mutant APE1 C65A. Our data suggest that the degradation of wild-type p53 is blocked when the redox domain of APE1 is masked or interrupted. Based on this evidence, we hereby report a novel mechanism of p53 degradation through an APE1-mediated, redox-dependent pathway.
•Genistein induces apoptosis via stabilizing p53 protein.•Genistein stabilizes p53 through targeting interaction between APE1 and p53.•The interaction between APE1 and p53 promotes p53 degradation.•The redox domain of APE1 is required for APE1–p53 interaction and p53 degradation.