title: Genistein induces apoptosis by stabilizing intracellular p53 protein through an APE1-mediated pathway.
abstract: 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.
authors.affiliation: Cancer Center, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, People's Republic of China.
authors.forename: Jianwu
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Cancer Center, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, People's Republic of China.
authors.forename: Chong
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Cancer Center, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, People's Republic of China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Qing
authors.affiliation: Cancer Center, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, People's Republic of China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Cancer Center, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, People's Republic of China.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Cancer Center, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, People's Republic of China. Electronic address: mengxia.li@outlook.com.
authors.forename: Mengxia
authors.initials: M
authors.lastname: Li
authors.affiliation: Cancer Center, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, People's Republic of China. Electronic address: yangzz1970@163.com.
authors.forename: Zhenzhou
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Cancer Center, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, People's Republic of China.
authors.forename: Dong
authors.initials: D
authors.lastname: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000378:metabolism*; D019833:Genistein / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D010084:Oxidation-Reduction; D055550:Protein Stability; D059748:Proteolysis; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53
chemical_list: D000970:Antineoplastic Agents; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D019833:Genistein; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase
keywords: APE1; Genistein; Stability; Wild-type p53