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Review
. 2012 Jan;5(1):36-53.
doi: 10.2174/1874467211205010036.

APE1/Ref-1 role in redox signaling: translational applications of _targeting the redox function of the DNA repair/redox protein APE1/Ref-1

Mark R Kelley  1 , Millie M Georgiadis, Melissa L Fishel
Affiliations
Review

APE1/Ref-1 role in redox signaling: translational applications of _targeting the redox function of the DNA repair/redox protein APE1/Ref-1

Mark R Kelley et al. Curr Mol Pharmacol. 2012 Jan.

Abstract

The heterogeneity of most cancers diminishes the treatment effectiveness of many cancer-killing regimens. Thus, treatments that hold the most promise are ones that block multiple signaling pathways essential to cancer survival. One of the most promising proteins in that regard is APE1, whose reduction-oxidation activity influences multiple cancer survival mechanisms, including growth, proliferation, metastasis, angiogenesis, and stress responses. With the continued research using APE1 redox specific inhibitors alone or coupled with developing APE1 DNA repair inhibitors it will now be possible to further delineate the role of APE1 redox, repair and protein-protein interactions. Previously, use of siRNA or over expression approaches, while valuable, do not give a clear picture of the two major functions of APE1 since both techniques severely alter the cellular milieu. Additionally, use of the redox-specific APE1 inhibitor, APX3330, now makes it possible to study how inhibition of APE1's redox signaling can affect multiple tumor pathways and can potentiate the effectiveness of existing cancer regimens. Because APE1 is an upstream effector of VEGF, as well as other molecules that relate to angiogenesis and the tumor microenvironment, it is also being studied as a possible treatment for agerelated macular degeneration and diabetic retinopathy. This paper reviews all of APE1's functions, while heavily focusing on its redox activities. It also discusses APE1's altered expression in many cancers and the therapeutic potential of selective inhibition of redox regulation, which is the subject of intense preclinical studies.

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Conflict of interest statement

CONFLICT OF INTEREST

The authors state that there are no conflicts of interest or any potential competing interests.

Figures

Fig. 1
Fig. 1
Two _targets in one protein. APE1 has both redox and repair activities that involve distinct sites and residues in the protein. On the left panel is a ribbon rendering of APE1 in gray with the two Cys residues implicated in the redox activity, C65 and C93, shown in black sticks. On the right panel is a similar rendering of APE1 with a DNA substrate shown as a cartoon rendering in dark gray with abasic site and adjacent bases shown in dark gray sticks. The repair active site specifically recognizes duplex DNA containing an abasic site. Functional activities associated with redox or repair activities are shown along with the expected consequences of inhibition of these functions.
Fig. 2
Fig. 2
Inhibition of APE1 redox mechanism affects multiple cancer pathway _targets. Blocking APE1 redox signaling affects various downstream _targets that can impact on tumor growth factors, angiogenesis, growth and proliferation and metastasis and migration of the tumor.
Fig. 3
Fig. 3
APE1 role in DNA base excision repair (BER). This figure gives a very general overview of the BER pathway and is discussed in more detail in other chapters in this review issue. A) Repair is initiated by a damage specific DNA glycosylase, which removes the damaged base to generate an AP site. Monofunctional DNA glycosylases remove the damaged base to generate an AP site (shown) whereas bifunctional glycosylases in addition to excising the damaged base also nick the phosphodiester backbone, 3′ to the AP site (not shown). APE1 processes the AP sites by hydrolyzing the backbone 5′ to the AP site to generate 3′OH and 5′ dRP groups. The 5′ dRP group is removed by the dRPase function of DNA Polymerase β and it also fills in the correct base. Repair is completed by DNA Ligase III/XRCC1 by sealing the nick. Failure to repair such accumulated AP sites leads to cytotoxicity, increased apoptosis. Elevated levels of APE1 in cancer cells have been linked to resistance to chemotherapy, poor prognosis and survival. Thus inhibiting APE1 leads to sensitization of cancer cells to chemotherapeutic agents [26]. B) In the major short-patch (SP) BER pathway regular AP sites are repaired by the removal of the single damaged base. Modified or oxidized AP sites are repaired by the long-patch (LP) BER pathway where a flap of 3–8 nucleotides is displaced and excised by Fen1. DNA polymerase β, δ or ε then inserts the correct nucleotides and repair is completed by sealing of the nick by DNA ligase I. APE1 also interacts with PCNA in the LP BER pathway [26].
Fig. 4
Fig. 4
Inhibition of APE1 redox signaling is predicted to inhibit downstream disease-specific genes of the TFs it regulates. In this figure, three of seven identified relevant TFs for pancreatic cancer are shown [53]. All are _targets of APE1 redox signaling and inhibiting this function should lead to altered responses [25, 27].
Fig. 5
Fig. 5
Role of APE1 on tumor microenvironment. As an example, blocking APE1 function could lead to a variety of alterations not only in the tumor, but also in the tumor microenvironment including decreased angiogenesis, inhibition of NFkB associated with macrophages and inflammation as well as the TF _targets and effects in the tumor [53]. The redox inhibitor APX3330 and analogs have the potential to block all of these various aspects of APE1 signaling pathways in tumors and the surrounding microenvironment [, , , –109, 116].
Fig. 6
Fig. 6
Inhibiting APE1 as a multi-prong approach for cancer and other indications. Blocking APE1 redox and DNA repair functions should provide multiple approaches for small molecule inhibitors of these functions in a variety of cancer and other indications. With the recent data supporting a role of APE1 in angiogenesis [, , –111], a wide variety of indications such as AMD, ROP, diabetic retinopathy and others are potential disease areas for APE1 redox inhibition. APE1 DNA repair inhibition is more _targeted toward cancer uses alone or with chemotherapeutic agents and ionizing radiation [37, 114, 121, 168].
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