Revisiting Two Decades of Research Focused on Targeting APE1 for Cancer Therapy: The Pros and Cons

Abstract

APE1 is an essential endodeoxyribonuclease of the base excision repair pathway that maintains genome stability. It was identified as a pivotal factor favoring tumor progression and chemoresistance through the control of gene expression by a redox-based mechanism. APE1 is overexpressed and serum-secreted in different cancers, representing a prognostic and predictive factor and a promising non-invasive biomarker. Strategies directly targeting APE1 functions led to the identification of inhibitors showing potential therapeutic value, some of which are currently in clinical trials. Interestingly, evidence indicates novel roles of APE1 in RNA metabolism that are still not fully understood, including its activity in processing damaged RNA in chemoresistant phenotypes, regulating onco-miRNA maturation, and oxidized RNA decay. Recent data point out a control role for APE1 in the expression and sorting of onco-miRNAs within secreted extracellular vesicles. This review is focused on giving a portrait of the pros and cons of the last two decades of research aiming at the identification of inhibitors of the redox or DNA-repair functions of APE1 for the definition of novel targeted therapies for cancer. We will discuss the new perspectives in cancer therapy emerging from the unexpected finding of the APE1 role in miRNA processing for personalized therapy.

Keywords: APE1; cancer; inhibitors.

Figure 1

Human APE1 structure and its key residues. A schematic representation of the primary sequence of APE1, in which the most important aminoacids are highlighted. In the first 33 residues required for protein-protein interaction, residues K6 and K7 (green, ο) are involved in the shuttling between the nucleus and the cytoplasm. Residues K27, K31, K32, and K35 are essential for proteosomal cleavage. All the above mentioned lysine residues can also be acetylated. The redox regulatory region is included between aminoacids 35 and 125, in which the main residues involved are C65, C93, and C99 (red). The endonuclease domain spans between 65 and 318 (residues indicated in blue, •). Specifically, E96 is involved in divalent metal coordination, while D210 and H309 have functions in the hydrolytic reaction. Other important residues in the endonuclease domain are D70, which is implicated in the 3′-phosphodiesterase activity; K98, important for the nucleotide incision repair (NIR); and F266, which is involved in the 3′-5′ exonuclease activity. Lastly, P112L, D148E, R193C/H, R237C, and H298Y/Q (yellow, ο) are some of the polymorphisms of APE1 that will be discussed in this review. Below, the tridimensional structure of APE1 is reported (PDB ID: 7SVB). Created with BioRender.com (accessed on 31 May 2023).

Figure 2

Illustration of the main functions of APE1 and its relative inhibitors. The DNA repair mediated by the endonuclease activity of APE1 is inhibited by Methoxyamine, APE Inhibitor III, and Gossypol (blue blunt arrows). The gene expression promoted by the redox activity of APE1 on TFs is inhibited by Gossypol, curcumin, resveratrol, and APX3330 (green blunt arrows). Especially through its N-terminal region, APE1 is involved in several PPIs, including Nucleophosmin 1 (NPM1). This interaction is inhibited by fiduxosin, SB 206553, and spiclomazine (fuchsia blunt arrows). Recent findings have shown that APE1 is secreted by EVs in the microambient and is involved in RNA metabolism, including the regulation of miRNA processing. If these novel features of APE1 can be inhibited, it is still unknown (brown blunt arrows) and an interesting starting point for future explorations. For each inhibitor, pillows are drawn when the inhibitor has been enrolled in one or more clinical trials. Created with BioRender.com (accessed on 31 May 2023).