The multifunctional APE1 protein is required for tumor progression and is associated with cancer resistance. It is shown that APE1 presents structural elements that function in distinct cellular roles, highlighting the molecular determinants of the multifunctional nature of this protein and providing the basis for a new role of the C65 residue.

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Highlights APE1 is overexpressed in colorectal cancer  The APE1-endonuclease inhibitor (Compound #3) promotes p53 activation in HCT-116 colon cancer cell line. Compound #3 triggers p53-mediated effects on cell metabolism in HCT-116 colon cancer cell line. Compound #3 affects mitochondrial activity and sensitises cells to genotoxic treatment in a p53-dependent manner. 3D organoids derived from colorectal cancer patients are susceptible to Compound #3 in a p53-status correlated manner. Bioinformatics analyses support the hypothesis to target mitochondrial function in cancer cells through APE1-endonuclease inhibitors. Further studies are needed to test the possibility to target the endonuclease activity of APE1 in colorectal cancer.

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