Exploiting the Ref-1-APE1 node in cancer signaling and other diseases: from bench to clinic

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.

APE1/Ref‐1 knockdown in pancreatic ductal adenocarcinoma – characterizing gene expression changes and identifying novel pathways using single‐cellRNAsequencing

“…Further analysis into the viability of the mitochondrial dysfunction and other affected pathways identified in this study as potential APE1‐based combination therapy targets is ongoing. Additionally, these results support the role of APE1 as a node in cancer signaling (Shah et al ., 2017). …”

“…ITGA1, part of the integrin signaling and virus entry via endocytic pathways as identified by IPA, is involved in cell proliferation (Macias‐Perez et al ., 2008) and invasion (Yang et al ., 2015), as well as inflammation (Becker et al ., 2013) and fibrosis (Ramos et al ., 2012), which have all been previously linked to APE1 (Aamann et al ., 2016; Shah et al ., 2017). …”

Potential role of cancer stem cells as biomarkers and therapeutic targets in cervical cancer

“…Exposure to ionizing radiation or platinum compounds causes DNA damage that leads to formation of reactive oxygen species (ROS), which stimulate AP endonuclease activity. This leads to an increased expression of Ape1/Ref‐1 . It was observed that the cancer cells with primary or secondary resistance to the DNA damaging agents have an overexpression of Ape1/Ref‐1.…”

“…Hence, Ape1/Ref‐1 can be responsible for primary resistance in patients. Studies show that p53‐regulated Ape1/Ref‐1 and ROS are crucial in the self‐renewal, differentiation, and survival of CSCs (Figure ) …”

“…Hence, Ape1/Ref-1 can be responsible for primary resistance in patients. Studies show that p53-regulated Ape1/Ref-1 and ROS are crucial in the self-renewal, differentiation, and survival of CSCs(Figure 2) 60,72,[78][79][80]. Targeting CCSC for cervical cancer therapy is relatively new, and CSC targeting therapies are still evolving, the detailed mechanistic of which remains elusive.…”