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      Inhibitors of the apurinic/apyrimidinic endonuclease 1 (APE1)/nucleophosmin (NPM1) interaction that display anti-tumor properties

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          Abstract

          The apurinic/apyrimidinic endonuclease 1 (APE1) is a protein central to the base excision DNA repair pathway and operates in the modulation of gene expression through redox-dependent and independent mechanisms. Aberrant expression and localization of APE1 in tumors are recurrent hallmarks of aggressiveness and resistance to therapy. We identified and characterized the molecular association between APE1 and nucleophosmin (NPM1), a multifunctional protein involved in the preservation of genome stability and rRNA maturation. This protein-protein interaction modulates subcellular localization and endonuclease activity of APE1. Moreover, we reported a correlation between APE1 and NPM1 expression levels in ovarian cancer, with NPM1 overexpression being a marker of poor prognosis. These observations suggest that tumors that display an augmented APE1/NPM1 association may exhibit increased aggressiveness and resistance. Therefore, targeting the APE1/NPM1 interaction might represent an innovative strategy for the development of anticancer drugs, as tumor cells relying on higher levels of APE1 and NPM1 for proliferation and survival may be more sensitive than untransformed cells.

          We set up a chemiluminescence-based high-throughput screening assay in order to find small molecules able to interfere with the APE1/NPM1 interaction. This screening led to the identification of a set of bioactive compounds that impair the APE1/NPM1 association in living cells. Interestingly, some of these molecules display anti-proliferative activity and sensitize cells to therapeutically relevant genotoxins. Given the prognostic significance of APE1 and NPM1, these compounds might prove effective in the treatment of tumors that show abundant levels of both proteins, such as ovarian or hepatic carcinomas.

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          Author and article information

          Journal
          8811105
          1399
          Mol Carcinog
          Mol. Carcinog.
          Molecular carcinogenesis
          0899-1987
          1098-2744
          3 March 2015
          11 April 2015
          May 2016
          01 May 2017
          : 55
          : 5
          : 688-704
          Affiliations
          [1 ]Department of Medical and Biological Sciences, University of Udine, Udine, Italy
          [2 ]NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD – USA
          [3 ]Department of Pharmacy, CIRPEB (Centro Interuniversitario di Ricerca sui Peptidi Bioattivi), University of Naples ‘Federico II’, Naples, Italy
          [4 ]Center for Advanced Biomaterials for Healthcare@CRIB, Istituto Italiano di Tecnologia (IIT), Naples, Italy
          [5 ]Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD – USA
          Author notes
          Correspondence to: Prof. Gianluca Tell, Department of Medical and Biological Sciences, University of Udine, P.le Kolbe 4, 33100 Udine, Italy, Tel.: ++39 0432 494311; Fax ++39 0432 494301. gianluca.tell@ 123456uniud.it . Dr. Anton Simeonov, NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD – USA. asimeono@ 123456mail.nih.gov
          Article
          PMC4600639 PMC4600639 4600639 nihpa668166
          10.1002/mc.22313
          4600639
          25865359
          7b52c39a-675b-41b3-b6bb-66689dae8bed
          History
          Categories
          Article

          APE1,NPM1,protein/protein interaction,small molecule,combination therapy

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