Inhibition of APE1-endonuclease activity affects cell metabolism in colon cancer cells via a p53-dependent pathway.

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.

• Authors: Marta Codrich, Marina Comelli, Matilde Clarissa Malfatti, Catia Mio, Dilara Ayyildiz, Chi Zhang, Mark R Kelley, Giovanni Terrosu, Carlo E M Pucillo, Gianluca Tell
• Journal: DNA repair (DNA Repair (Amst)) Vol. 82 Pg. 102675 (10 2019) ISSN: 1568-7856 [Electronic] Netherlands
• PMID: 31450087 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier B.V. All rights reserved.

Chemical References

• Enzyme Inhibitors
• NPM1 protein, human
• Tumor Suppressor Protein p53
• Nucleophosmin
• Methyl Methanesulfonate
• APEX1 protein, human
• DNA-(Apurinic or Apyrimidinic Site) Lyase

Topics

• Colonic Neoplasms (pathology)
• DNA Damage
• DNA-(Apurinic or Apyrimidinic Site) Lyase (antagonists & inhibitors)
• Enzyme Inhibitors (pharmacology)
• Gene Expression Regulation, Neoplastic (drug effects)
• HCT116 Cells
• Humans
• Methyl Methanesulfonate (pharmacology)
• Mitochondria (drug effects, metabolism)
• Mutation
• Nucleophosmin
• Tumor Suppressor Protein p53 (genetics, metabolism)