{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T09:28:47Z","timestamp":1778232527696,"version":"3.51.4"},"reference-count":36,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2022,8,12]],"date-time":"2022-08-12T00:00:00Z","timestamp":1660262400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research Foundation of Korea (NRF) funded by the Ministry of Education","award":["2014R1A6A1029617 B.J."],"award-info":[{"award-number":["2014R1A6A1029617 B.J."]}]},{"name":"National Research Foundation of Korea (NRF) funded by the Ministry of Education","award":["2016R1D1A1B01009752 S.C."],"award-info":[{"award-number":["2016R1D1A1B01009752 S.C."]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The simultaneous regulation of cancer cells and inflammatory immune cells in the tumor microenvironment (TME) can be an effective strategy in treating aggressive breast cancer types, such as triple-negative breast cancer (TNBC). Apurinic\/apyrimidinic endonuclease 1\/redox effector factor 1 (APE1\/Ref-1) is a multi-functional nuclear protein that can be stimulated and then secreted. The extracellular APE1\/Ref-1 causes a reduction in disulfide bonds in cytokine receptors, resulting in their conformational changes, thereby inhibiting inflammatory signaling. Furthermore, the secreted APE1\/Ref-1 in response to acetylation has been shown to bind to a receptor for the advanced glycation end product (RAGE), initiating the apoptotic cell death of TNBC in vitro and in vivo. This study used PPTLS-APE1\/Ref-1 in an adenovirus vector (Ad-PPTLS-APE1\/Ref-1) for the constant expression of extracellular APE1\/Ref-1, and our results demonstrated its dual function as an apoptotic initiator and inflammation regulator. Injecting MDA-MB 231 orthotopic xenografts with the Ad-PPTLS-APE1\/Ref-1 inhibited tumor growth and development in response to acetylation. Moreover, Ad-PPTLS-APE1\/Ref-1 generated reactive oxygen species (ROS), and tumor tissues derived from these xenografts exhibited apoptotic bodies. Compared to normal mice, a comparable ratio of anti- and pro-inflammatory cytokines was observed in the plasma of Ad-PPTLS-APE1\/Ref-1-injected mice. Mechanistically, the disturbed cytokine receptor by reducing activity of PPTLS-APE1\/Ref-1 inhibited inflammatory signaling leading to the inactivation of the p21-activated kinase 1-mediated signal transducer and activator of transcription 3\/nuclear factor-\u03baB axis in tumor tissues. These results suggest that the regulation of inflammatory signaling with adenoviral-mediated PPTLS-APE1\/Ref-1 in tumors modulates the secretion of pro-inflammatory cytokines in TME, thereby inhibiting aggressive cancer cell progression, and could be considered as a promising and safe therapeutic strategy for treating TNBCs.<\/jats:p>","DOI":"10.3390\/ijms23169021","type":"journal-article","created":{"date-parts":[[2022,8,15]],"date-time":"2022-08-15T01:47:21Z","timestamp":1660528041000},"page":"9021","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Dual Function of Secreted APE1\/Ref-1 in TNBC Tumorigenesis: An Apoptotic Initiator and a Regulator of Chronic Inflammatory Signaling"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3358-7923","authenticated-orcid":false,"given":"Sunga","family":"Choi","sequence":"first","affiliation":[{"name":"Department of Bioinformatics and Biosystems, Seongnam Campus of Korea Polytechnics, Seongnam-si 13122, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu-Ran","family":"Lee","sequence":"additional","affiliation":[{"name":"Research Institute of Medical Sciences, College of Medicine, Chungnam National University, Daejeon 35015, Korea"},{"name":"Department of Medical Science, College of Medicine, Chungnam National University, Daejeon 35015, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ki-Mo","family":"Kim","sequence":"additional","affiliation":[{"name":"Korean Medicine Convergence Research Division, Korea Institute of Oriental Medicine (KIOM), Daejeon 34054, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Euna","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Biology, Union University, Jackson, TN 38305, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3347-2739","authenticated-orcid":false,"given":"Byeong-Hwa","family":"Jeon","sequence":"additional","affiliation":[{"name":"Research Institute of Medical Sciences, College of Medicine, Chungnam National University, Daejeon 35015, Korea"},{"name":"Department of Medical Science, College of Medicine, Chungnam National University, Daejeon 35015, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"6100","DOI":"10.1158\/1078-0432.CCR-10-1533","article-title":"Intrinsic breast tumor subtypes, race, and long-term survival in the Carolina Breast Cancer Study","volume":"16","author":"Cole","year":"2010","journal-title":"Clin. Cancer Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1038\/35021093","article-title":"Molecular portraits of human breast tumours","volume":"406","author":"Perou","year":"2000","journal-title":"Nature"},{"key":"ref_3","first-page":"98","article-title":"Chronic inflammation in cancer development","volume":"2","author":"Multhoff","year":"2011","journal-title":"Front. Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1038\/ni.2060","article-title":"Inflammation meets cancer, with NF-kappaB as the matchmaker","volume":"12","author":"Karin","year":"2011","journal-title":"Nat. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/j.ccr.2004.08.012","article-title":"Inhibition of NF-kappaB in cancer cells converts inflammation-induced tumor growth mediated by TNFalpha to TRAIL-mediated tumor regression","volume":"6","author":"Luo","year":"2004","journal-title":"Cancer Cell"},{"key":"ref_6","first-page":"1","article-title":"The diverse roles of the TNF axis in cancer progression and metastasis","volume":"11","author":"Ham","year":"2016","journal-title":"Trends Cancer Res."},{"key":"ref_7","first-page":"267","article-title":"Regulation of ovarian carcinoma SKOV-3 cell proliferation and secretion of MMPs by autocrine IL-6","volume":"27","author":"Rabinovich","year":"2007","journal-title":"Anticancer Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2548","DOI":"10.1038\/sj.onc.1203551","article-title":"Roles of STAT3 in mediating the cell growth, differentiation and survival signals relayed through the IL-6 family of cytokine receptors","volume":"19","author":"Hirano","year":"2000","journal-title":"Oncogene"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1016\/j.cell.2008.03.039","article-title":"Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network","volume":"133","author":"Kuilman","year":"2008","journal-title":"Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e8840","DOI":"10.1097\/MD.0000000000008840","article-title":"Association between serum cytokines and progression of breast cancer in Chinese population","volume":"96","author":"Wang","year":"2017","journal-title":"Medicine"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.1056\/NEJM200005043421807","article-title":"Role of transforming growth factor beta in human disease","volume":"342","author":"Blobe","year":"2000","journal-title":"N. Engl. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3470","DOI":"10.1158\/0008-5472.CAN-12-4524-T","article-title":"Growth of triple-negative breast cancer cells relies upon coordinate autocrine expression of the proinflammatory cytokines IL-6 and IL-8","volume":"73","author":"Hartman","year":"2013","journal-title":"Cancer Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"411","DOI":"10.3390\/ijms14010411","article-title":"TNF-alpha gene knockout in triple negative breast cancer cell line induces apoptosis","volume":"14","author":"Pileczki","year":"2012","journal-title":"Int. J. Mol. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4493","DOI":"10.1158\/0008-5472.CAN-15-3435","article-title":"Preclinical Efficacy of Bevacizumab with CRLX101, an Investigational Nanoparticle-Drug Conjugate, in Treatment of Metastatic Triple-Negative Breast Cancer","volume":"76","author":"Pham","year":"2016","journal-title":"Cancer Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1571","DOI":"10.1002\/jcp.25685","article-title":"A Real-World Multicentre Retrospective Study of Paclitaxel-Bevacizumab and Maintenance Therapy as First-Line for HER2-Negative Metastatic Breast Cancer","volume":"232","author":"Gamucci","year":"2017","journal-title":"J. Cell Physiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1089\/ars.2008.2194","article-title":"The many functions of APE1\/Ref-1: Not only a DNA repair enzyme","volume":"11","author":"Tell","year":"2009","journal-title":"Antioxid. Redox Signal."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"36","DOI":"10.2174\/1874467211205010036","article-title":"APE1\/Ref-1 role in redox signaling: Translational applications of targeting the redox function of the DNA repair\/redox protein APE1\/Ref-1","volume":"5","author":"Kelley","year":"2012","journal-title":"Curr. Mol. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"793096","DOI":"10.3389\/fimmu.2022.793096","article-title":"APE1\/Ref-1 Role in Inflammation and Immune Response","volume":"13","author":"Oliveira","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"23383","DOI":"10.18632\/oncotarget.4345","article-title":"Extracellularly secreted APE1\/Ref-1 triggers apoptosis in triple-negative breast cancer cells via RAGE binding, which is mediated through acetylation","volume":"6","author":"Lee","year":"2015","journal-title":"Oncotarget"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"8701","DOI":"10.1038\/s41598-018-27025-9","article-title":"Therapeutic positioning of secretory acetylated APE1\/Ref-1 requirement for suppression of tumor growth in triple-negative breast cancer in vivo","volume":"8","author":"Lee","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1007\/s10059-013-0195-6","article-title":"Cytoplasmic localization and redox cysteine residue of APE1\/Ref-1 are associated with its anti-inflammatory activity in cultured endothelial cells","volume":"36","author":"Park","year":"2013","journal-title":"Mol. Cells"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"23015","DOI":"10.1038\/srep23015","article-title":"Secreted APE1\/Ref-1 inhibits TNF-alpha-stimulated endothelial inflammation via thiol-disulfide exchange in TNF receptor","volume":"6","author":"Park","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_23","first-page":"1","article-title":"APE1\/Ref-1 with reducing activity induces mesenchymal-to-epithelial transition in TNF-\u03b1-stimulated breast cancer cells","volume":"9","author":"Choi","year":"2022","journal-title":"Integr. Cancer Sci. Ther."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.freeradbiomed.2019.05.013","article-title":"The extracellular role of Ref-1 as anti-inflammatory function in lipopolysaccharide-induced septic mice","volume":"139","author":"Joo","year":"2019","journal-title":"Free Radic. Biol. Med."},{"key":"ref_25","first-page":"824","article-title":"Elevated and altered expression of the multifunctional DNA base excision repair and redox enzyme Ape1\/ref-1 in prostate cancer","volume":"7","author":"Kelley","year":"2001","journal-title":"Clin. Cancer Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1038\/bjc.1998.194","article-title":"Human AP endonuclease 1 (HAP1) protein expression in breast cancer correlates with lymph node status and angiogenesis","volume":"77","author":"Kakolyris","year":"1998","journal-title":"Br. J. Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1136\/gutjnl-2014-306768","article-title":"Tracing PAKs from GI inflammation to cancer","volume":"63","author":"Dammann","year":"2014","journal-title":"Gut"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"42","DOI":"10.3390\/diseases6020042","article-title":"Viral Vectors in Gene Therapy","volume":"6","author":"Lundstrom","year":"2018","journal-title":"Diseases"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1080\/14712598.2017.1338684","article-title":"Viral gene therapy for breast cancer: Progress and challenges","volume":"17","author":"Asad","year":"2017","journal-title":"Expert Opin. Biol. Ther."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"137","DOI":"10.2217\/14796694.2.1.137","article-title":"Current developments in adenovirus-based cancer gene therapy","volume":"2","author":"Rein","year":"2006","journal-title":"Future Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/j.bbrc.2013.04.101","article-title":"Histone deacetylases inhibitor trichostatin A modulates the extracellular release of APE1\/Ref-1","volume":"435","author":"Choi","year":"2013","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1517\/14728222.2010.492779","article-title":"PAK1 as a therapeutic target","volume":"14","author":"Kichina","year":"2010","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3397","DOI":"10.1038\/onc.2011.515","article-title":"PAK1 is a breast cancer oncogene that coordinately activates MAPK and MET signaling","volume":"31","author":"Shrestha","year":"2012","journal-title":"Oncogene"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"42555","DOI":"10.1038\/srep42555","article-title":"A novel orally bioavailable compound KPT-9274 inhibits PAK4, and blocks triple negative breast cancer tumor growth","volume":"7","author":"Rane","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1314","DOI":"10.1038\/embor.2009.243","article-title":"IKK\/NF-kappaB and STAT3 pathways: Central signalling hubs in inflammation-mediated tumour promotion and metastasis","volume":"10","author":"Bollrath","year":"2009","journal-title":"EMBO Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"14745","DOI":"10.1073\/pnas.1618582114","article-title":"Growth hormone-releasing hormone receptor antagonists inhibit human gastric cancer through downregulation of PAK1-STAT3\/NF-kappaB signaling","volume":"113","author":"Gan","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/16\/9021\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:07:52Z","timestamp":1760141272000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/16\/9021"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,12]]},"references-count":36,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2022,8]]}},"alternative-id":["ijms23169021"],"URL":"https:\/\/doi.org\/10.3390\/ijms23169021","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,12]]}}}