Genistein induces apoptosis by stabilizing intracellular p53 protein through an APE1-mediated pathway |
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| Institution: | 1. Diabetes Research Group, SAAD Centre for Pharmacy & Diabetes, University of Ulster, Coleraine, Northern Ireland, BT52 1SA, UK;2. Institute of Clinical Biochemistry, Hannover Medical School, 30625, Hannover, Germany;3. Institute of Food Sciences, National Research Council, Avellino, Italy;4. Department of Pharmacognosy, Faculty of Pharmacy, Gazi University, Ankara, Turkey;5. Pharmacognosy Research Laboratories, Medway School of Science, University of Greenwich, Chatham-Maritime, United Kingdom;6. Department of Drug Sciences, Medicinal Chemistry and Pharmaceutical Technology Section, University of Pavia, Pavia, Italy;7. Research Group on Community Nutrition and Oxidative Stress and CIBERobn (Physiopathology of Obesity and Nutrition), University of Balearic Islands, Palma de Mallorca, Spain;8. Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran;9. Department of Biotechnology, Alagappa University, Karaikudi, Tamil Nadu, India;10. Department of Pharmacy, Health, and Nutritional Sciences, University of Calabria, Rende, Italy;1. Department of Urology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China;2. Department of Surgical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China;3. Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China;4. Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA;1. Tunneling Group, Biotechnology Centre, Silesian University of Technology, 8 Krzywoustego St, 44-100 Gliwice, Poland;2. Department of Organic Chemistry, Bioorganic Chemistry and Biotechnology, Silesian University of Technology, 4 Krzywoustego St, 44-100 Gliwice, Poland;3. Department for Experimental Medicine, Medical University of Silesia, 4 Medyków St, 40-752 Katowice, Poland;4. Center for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch 15 Wybrze?e Armii Krajowej St, 44-102 Gliwice, Poland;1. Department of Pharmacy, The People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, 530021, People’s Republic of China;2. Department of Radiation Oncology of the Clinical Cancer Center, The People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, 530021, People’s Republic of China |
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| 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. |
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| Keywords: | Wild-type p53 Stability APE1 Genistein |
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