APE1/Ref-1 as an emerging therapeutic target for various human diseases: phytochemical modulation of its functions

Abstract

Apurinic/apyrimidinic endonuclease 1 (APE1) is a multifunctional enzyme involved in the base excision repair (BER) pathway, which repairs oxidative base damage caused by endogenous and exogenous agents. APE1 acts as a reductive activator of many transcription factors (TFs) and has also been named redox effector factor 1, Ref-1. For example, APE1 activates activator protein-1, nuclear factor kappa B, hypoxia-inducible factor 1α, paired box gene 8, signal transducer activator of transcription 3 and p53, which are involved in apoptosis, inflammation, angiogenesis and survival pathways. APE1/Ref-1 maintains cellular homeostasis (redox) via the activation of TFs that regulate various physiological processes and that crosstalk with redox balancing agents (for example, thioredoxin, catalase and superoxide dismutase) by controlling levels of reactive oxygen and nitrogen species. The efficiency of APE1/Ref-1's function(s) depends on pairwise interaction with participant protein(s), the functions regulated by APE1/Ref-1 include the BER pathway, TFs, energy metabolism, cytoskeletal elements and stress-dependent responses. Thus, APE1/Ref-1 acts as a 'hub-protein' that controls pathways that are important for cell survival. In this review, we will discuss APE1/Ref-1's versatile nature in various human etiologies, including neurodegeneration, cancer, cardiovascular and other diseases that have been linked with alterations in the expression, subcellular localization and activities of APE/Ref-1. APE1/Ref-1 can be targeted for therapeutic intervention using natural plant products that modulate the expression and functions of APE1/Ref-1. In addition, studies focusing on translational applications based on APE1/Ref-1-mediated therapeutic interventions are discussed.

Figure 1

The role of apurinic/apyrimidinic endonuclease 1 (APE1)/redox effector factor-1 (Ref-1) in maintaining genome integrity in response to reactive oxygen species/reactive nitrogen species (ROS/RNS)-mediated oxidative stress associated with various human diseases and the possible intervention of phytochemicals toward the functional modulation of APE1/Ref-1. ROS/RNS from endogenous and exogenous sources cause oxidative stress in various cell types; in response to this stress, APE1/Ref-1 dual functions (repair and redox) are activated as a part of the DNA repair response through the base excision repair (BER) pathway to maintain the genomic integrity of the cell and the redox regulation of various transcription factors (TFs) in cell-survival pathways. Natural plant products hold the potential to modulate the expression and functions of APE1/Ref-1, thus representing a promising therapeutic intervention against various human diseases including cancer, cardiovascular and neurodegenerative disorders. EGCG, epigallocatechingallate; UV, ultraviolet.

Figure 2

Stress-induced prismatic functions of apurinic/apyrimidinic endonuclease 1 (APE1)/redox effector factor-1 (Ref-1) in different cell types during disease conditions. Activation of APE1/Ref-1 occurs because of various external and internal stimulating factors (for example, radiation, reactive oxygen species/reactive nitrogen species (ROS/RNS) and hypoxia). In addition, many misfolded proteins, namely, amyloid beta (Aβ), α- synuclein, Tau and PrP^sc, also cause APE1/Ref-1 activation. Further increases in [Ca²⁺]_i also induce APE1/Ref-1 expression in various cell types. Upregulation of APE1/Ref-1 further activates various proteins either directly or indirectly and controls and modulates various key biological functions including DNA repair, cellular redox balance, cell proliferation, cytoskeleton modification and energy metabolism.

Figure 3

A schematic representation of the mechanism of the short-patch (SN-BER) and long-patch (LP-BER) sub-pathways of base excision repair (BER) in mammalian cells. apurinic/apyrimidinic endonuclease 1 (APE1)/redox effector factor-1 (Ref-1) functions as an AP endonuclease in SN-BER, initiated by monofunctional DNA glycosylase (DG), and as a 3′phosphodiesterase in LP-BER, initiated by bifunctional DG. Pol β, X-ray repair cross-complementing protein 1 (XRCC1) and ligase III are required for SN-BER to conduct SN repair, whereas proliferating cell nuclear antigen (PCNA), Pol δ/ɛ, flap endonuclease 1 (FEN-1) and ligase I are required for LP-BER to conduct multinucleotide repair in mammalian cells.

Figure 4

Amyloid beta (Aβ)-induced neurotoxic responses enhance the association of key neuronal proteins with apurinic/apyrimidinic endonuclease 1 (APE1)/redox effector factor-1 (Ref-1). APE1/Ref-1-interacting proteins that are differentially expressed after treatment of PC12 neuronal cells with Aβ (25–35) peptide include cytoskeleton elements such as tropomodulin 3 (Tmod3) and the tropomyosin alpha-3 chain; energy metabolism proteins such as pyruvate kinase M2 (PKM2); N-acetyltransferase; sulfotransferase1c; and stress-responsive proteins such as leucine-rich and death domains, anti-NGF 30 and heterogenous nuclear ribonucleoprotein-H1 (hnRNP-H1).

Figure 5

Apurinic/apyrimidinic endonuclease 1 (APE1)/redox effector factor-1 (Ref-1) has a pivotal role in various human diseases. Owing to its vital role in the BER pathway, in balancing intra-cellular redox states and in the reductive activation of various transcription factors (TFs) controlling cell survival pathways, alterations in APE1/Ref-1 expression and functions have a crucial role in various human diseases including cancer, cardiovascular disease (CVD) and neurodegenerative diseases (NDs). The overexpression and enhanced enzymatic activities of APE1/Ref-1 have been linked with the conferral of survival advantage and chemoresistance in cancer cells. APE1/Ref-1 also has an important role in CVD by governing H-Ras-mediated endothelial nitric oxide synthase (eNOS) activity and NO bioavailability. In NDs, such as Alzheimer's disease (AD), Parkinson's disease (PD) and amyotropic lateral sclerosis (ALS), decreased neuronal expression of APE1/Ref-1 after neuronal insult decreases cell viability and promotes neurodegeneration. In addition to alterations in the expression of APE1/Ref-1 and its subcellular localization and enzymatic functions, single-nucleotide polymorphisms (SNPs) in the APE1/Ref-1 gene have been also reported to have a role in ALS, AD and cancer. In addition, various post-translational modifications (PTMs), such as acetylation, ubiquitination,^, s-nitrosylation, sumoylation and phosphorylation, have been demonstrated to regulate APE1/Ref-1 functions in various human diseases.