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

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.