Exp Mol Med.  2014 Jul;46(7):e106. 10.1038/emm.2014.42.

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

• Thakur S
• Sarkar B
• Cholia RP
• Gautam N
• Dhiman M
• Mantha AK

• KMID: 2155371
• DOI: http://doi.org/10.1038/emm.2014.42

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 1alpha, 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.

Keyword

Alzheimer's disease; APE1/Ref-1; base excision repair; cancer therapeutics; neurodegenerative diseases; phytochemicals

MeSH Terms

Animals
DNA Damage
DNA Repair
DNA-(Apurinic or Apyrimidinic Site) Lyase/analysis/genetics/*metabolism
Humans
*Molecular Targeted Therapy/methods
Neoplasms/*drug therapy/genetics/*metabolism
Neurodegenerative Diseases/*drug therapy/genetics/*metabolism
Oxidative Stress
Phytochemicals/pharmacology/*therapeutic use
Polymorphism, Genetic
Protein Interaction Maps
Phytochemicals
Apurinic or Apyrimidinic Site) Lyase