Inhibition of APE1-endonuclease activity affects cell metabolism in colon cancer cells via a p53-dependent pathway |
| |
| Affiliation: | 1. Laboratory of Molecular Biology and DNA Repair, Department of Medicine, University of Udine, Udine, 33100, Italy;2. Laboratory of Bioenergetics, Department of Medicine, University of Udine, Udine, 33100, Italy;3. Institute of Medical Genetics, Department of Medicine, University of Udine, Udine, 33100, Italy;4. Department of Medical and Molecular Genetics, Center for Computational Biology and Bioinformatics, Indiana University, School of Medicine, Indianapolis, IN 46202, USA;5. Herman B Wells Center for Pediatric Research, Department of Pediatrics and Pharmacology & Toxicology, Indiana University, School of Medicine, Indianapolis, IN 46202, USA;6. General Surgery and Transplantation Unit, Department of Medicine, University of Udine, Udine, 33100, Italy;7. Laboratory of Immunology, Department of Medicine, University of Udine, Udine, 33100, Italy;1. Ribeirão Preto Medical School, University of São Paulo, Department of Surgery and Anatomy, Av. Bandeirantes, 3900, Monte Alegre, Ribeirão Preto, São Paulo 14048-900, Brazil;2. Ribeirao Preto College of Nursing, University of São Paulo, Department of Maternal-Infant Nursing and Public Health, Av. Bandeirantes, 3900, Monte Alegre, Ribeirão Preto, São Paulo 14048-900, Brazil;3. Ribeirão Preto Medical School, University of São Paulo, Department of Internal Medicine, Av, Bandeirantes, 3900, Monte Alegre, Ribeirão Preto, São Paulo 14048-900, Brazil;1. CNRS UMR8200 – Genetic Stability and Oncogenesis, Université Paris-Sud, Paris-Saclay, Institut Gustave Roussy, Villejuif, France;2. Department of Biology, University of Copenhagen, DK-2200 Copenhagen N, Denmark;1. Laboratory of Molecular Biology and DNA Repair, Department of Medicine (DAME), University of Udine, Udine, Italy;2. Department of Pharmacy, University of Naples “Federico II”, Via D. Montesano 49, 80131, Naples, Italy;3. Department of Pharmacological Sciences, Stony Brook University, School of Medicine, Stony Brook, NY, 11794-8651, USA |
| |
| Abstract: | The pathogenesis of colorectal cancer (CRC) involves different mechanisms, such as genomic and microsatellite instabilities. Recently, a contribution of the base excision repair (BER) pathway in CRC pathology has been emerged. In this context, the involvement of APE1 in the BER pathway and in the transcriptional regulation of genes implicated in tumor progression strongly correlates with chemoresistance in CRC and in more aggressive cancers. In addition, the APE1 interactome is emerging as an important player in tumor progression, as demonstrated by its interaction with Nucleophosmin (NPM1). For these reasons, APE1 is becoming a promising target in cancer therapy and a powerful prognostic and predictive factor in several cancer types. Thus, specific APE1 inhibitors have been developed targeting: i) the endonuclease activity; ii) the redox function and iii) the APE1-NPM1 interaction. Furthermore, mutated p53 is a common feature of advanced CRC. The relationship between APE1 inhibition and p53 is still completely unknown. Here, we demonstrated that the inhibition of the endonuclease activity of APE1 triggers p53-mediated effects on cell metabolism in HCT-116 colon cancer cell line. In particular, the inhibition of the endonuclease activity, but not of the redox function or of the interaction with NPM1, promotes p53 activation in parallel to sensitization of p53-expressing HCT-116 cell line to genotoxic treatment. Moreover, the endonuclease inhibitor affects mitochondrial activity in a p53-dependent manner. Finally, we demonstrated that 3D organoids derived from CRC patients are susceptible to APE1-endonuclease inhibition in a p53-status correlated manner, recapitulating data obtained with HCT-116 isogenic cell lines. These findings suggest the importance of further studies aimed at testing the possibility to target the endonuclease activity of APE1 in CRC. |
| |
| Keywords: | Colorectal cancer BER APE1 APE1-inhibitors p53 Organoids |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
