PMID- 36674619 OWN - NLM STAT- MEDLINE DCOM- 20230124 LR - 20230816 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 24 IP - 2 DP - 2023 Jan 6 TI - Identification of Novel Pathways Regulated by APE1/Ref-1 in Human Retinal Endothelial Cells. LID - 10.3390/ijms24021101 [doi] LID - 1101 AB - APE1/Ref-1 (apurinic/apyrimidinic endonuclease 1, APE1 or APEX1; redox factor-1, Ref-1) is a dual-functional enzyme with crucial roles in DNA repair, reduction/oxidation (redox) signaling, and RNA processing and metabolism. The redox function of Ref-1 regulates several transcription factors, such as NF-kappaB, STAT3, HIF-1alpha, and others, which have been implicated in multiple human diseases, including ocular angiogenesis, inflammation, and multiple cancers. To better understand how APE1 influences these disease processes, we investigated the effects of APEX1 knockdown (KD) on gene expression in human retinal endothelial cells. This abolishes both DNA repair and redox signaling functions, as well as RNA interactions. Using RNA-seq analysis, we identified the crucial signaling pathways affected following APEX1 KD, with subsequent validation by qRT-PCR. Gene expression data revealed that multiple genes involved in DNA base excision repair, other DNA repair pathways, purine or pyrimidine metabolism signaling, and histidine/one carbon metabolism pathways were downregulated by APEX1 KD. This is in contrast with the alteration of pathways by APEX1 KD in human cancer lines, such as pancreatic ductal adenocarcinoma, lung, HeLa, and malignant peripheral nerve sheath tumors. These results highlight the unique role of APE1/Ref-1 and the clinical therapeutic potential of targeting APE1 and pathways regulated by APE1 in the eye. These findings provide novel avenues for ocular neovascularization treatment. FAU - Mijit, Mahmut AU - Mijit M AD - Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA. FAU - Liu, Sheng AU - Liu S AD - Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA. FAU - Sishtla, Kamakshi AU - Sishtla K AUID- ORCID: 0000-0002-1525-0155 AD - Department of Ophthalmology, Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA. FAU - Hartman, Gabriella D AU - Hartman GD AUID- ORCID: 0000-0002-2061-411X AD - Department of Ophthalmology, Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA. AD - Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA. FAU - Wan, Jun AU - Wan J AUID- ORCID: 0000-0001-9286-6562 AD - Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA. AD - Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA. FAU - Corson, Timothy W AU - Corson TW AUID- ORCID: 0000-0002-1402-7875 AD - Department of Ophthalmology, Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA. AD - Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA. AD - Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA. AD - Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. AD - Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. FAU - Kelley, Mark R AU - Kelley MR AUID- ORCID: 0000-0001-9472-1826 AD - Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA. AD - Department of Ophthalmology, Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA. AD - Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA. AD - Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. AD - Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. LA - eng GR - R01 CA205166/CA/NCI NIH HHS/United States GR - R01 HL140961/HL/NHLBI NIH HHS/United States GR - R01 CA231267/CA/NCI NIH HHS/United States GR - P30 CA082709/CA/NCI NIH HHS/United States GR - R01 EY031939/EY/NEI NIH HHS/United States GR - R01 CA167291/CA/NCI NIH HHS/United States PT - Journal Article DEP - 20230106 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - EC 4.2.99.18 (DNA-(Apurinic or Apyrimidinic Site) Lyase) RN - 0 (Transcription Factors) SB - IM MH - Humans MH - Endothelial Cells/metabolism MH - DNA-(Apurinic or Apyrimidinic Site) Lyase/genetics/metabolism MH - *Pancreatic Neoplasms/pathology MH - DNA Repair MH - Transcription Factors/metabolism MH - *Carcinoma, Pancreatic Ductal/genetics MH - Oxidation-Reduction PMC - PMC9865623 OTO - NOTNLM OT - APE1/Ref-1 OT - DNA repair OT - angiogenesis OT - gene expression OT - inflammation OT - ocular diseases OT - redox signaling COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2023/01/22 06:00 MHDA- 2023/01/25 06:00 PMCR- 2023/01/06 CRDT- 2023/01/21 01:25 PHST- 2022/11/09 00:00 [received] PHST- 2022/12/26 00:00 [revised] PHST- 2023/01/03 00:00 [accepted] PHST- 2023/01/21 01:25 [entrez] PHST- 2023/01/22 06:00 [pubmed] PHST- 2023/01/25 06:00 [medline] PHST- 2023/01/06 00:00 [pmc-release] AID - ijms24021101 [pii] AID - ijms-24-01101 [pii] AID - 10.3390/ijms24021101 [doi] PST - epublish SO - Int J Mol Sci. 2023 Jan 6;24(2):1101. doi: 10.3390/ijms24021101.