Abstract
Reduction-oxidation factor 1-apurinic/apyrimidinic endonuclease (Ref-1/APE1) is a critical node in tumor cells, both as a redox regulator of transcription factor activation and as part of the DNA damage response. As a redox signaling protein, Ref-1/APE1 enhances the transcriptional activity of STAT3, HIF-1α, nuclear factor kappa B, and other transcription factors to promote growth, migration, and survival in tumor cells as well as inflammation and angiogenesis in the tumor microenvironment. Ref-1/APE1 is activated in a variety of cancers, including prostate, colon, pancreatic, ovarian, lung and leukemias, leading to increased aggressiveness. Transcription factors downstream of Ref-1/APE1 are key contributors to many cancers, and Ref-1/APE1 redox signaling inhibition slows growth and progression in a number of tumor types. Ref-1/APE1 inhibition is also highly effective when paired with other drugs, including standard-of-care therapies and therapies targeting pathways affected by Ref-1/APE1 redox signaling. Additionally, Ref-1/APE1 plays a role in a variety of other indications, such as retinopathy, inflammation, and neuropathy. In this review, we discuss the functional consequences of activation of the Ref-1/APE1 node in cancer and other diseases, as well as potential therapies targeting Ref-1/APE1 and related pathways in relevant diseases. APX3330, a novel oral anticancer agent and the first drug to target Ref-1/APE1 for cancer is entering clinical trials and will be explored in various cancers and other diseases bringing bench discoveries to the clinic.
Highlights
Reduction-oxidation factor 1-apurinic/apyrimidinic endonuclease (Ref-1/APE1) is a critical node in tumor cells, both as a redox regulator of transcription factor activation and as part of the DNA damage response
Ref-1/APE1 expression is increased in many tumor types, and that change is associated with increased growth, migration, and drug resistance in tumor cells as well as decreased patient survival.[2, 3, 14, 21, 25, 26]
Further work is needed to explore the effects of Ref-1/APE1 redox signaling inhibition on hypoxia signaling, both alone and in combination with inhibitors of HIF, its cofactors, and/or the enzymes upregulated by HIF-mediated transcription
Summary
Exploiting the Ref-1-APE1 node in cancer signaling and other diseases: from bench to clinic. Because of the pathways it affects, Ref-1/APE1 is seen as a critical node in tumor signaling (Fig. 2) and is a prime target for anticancer therapy.[2, 3, 19, 21] teasing apart Ref-1/APE1’s activities to create a specific inhibitor that targets only its endonuclease or redox function is challenging. Exploiting the Ref-1-APE1 node in cancer signaling F Shah et al. Targets of Ref-1/APE1 redox signaling and control To understand Ref-1/APE1’s therapeutic potential, this section reviews its transcriptional targets, their normal and cancerinduced functions, any inhibitors in development, and Ref-1/ APE1’s activities on each protein. That is seen in pancreatic cancer cells, where simultaneous targeting of Ref-1/APE1 and STAT3 signaling, using npj Precision Oncology (2017) 19
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