{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T14:26:25Z","timestamp":1786112785803,"version":"build-2736575974"},"reference-count":41,"publisher":"S. Karger AG","issue":"1","license":[{"start":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T00:00:00Z","timestamp":1781827200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T00:00:00Z","timestamp":1781827200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pulse"],"abstract":"<jats:p>Introduction: DLL4-NOTCH1 signaling mediates juxtacrine communication between tip- and stalk-like endothelial cells during vascular sprouting, contributing to complementary aspects of endothelial function. Thus, simultaneous modulation of DLL4 and NOTCH1 may provide a strategy to broadly interfere with the endothelial functions involved in tumor angiogenesis. Accordingly, this study aimed to identify a novel natural compound capable of modulating DLL4-NOTCH1-mediated endothelial communication and to investigate how such modulation influences tumor angiogenesis and growth. Methods: We screened 66 natural compounds to identify those that suppress DLL4 and NOTCH1 signaling in endothelial cells. Using a dual-reporter system that combines a DLL4 promoter-driven reporter and a CSL luciferase reporter, we simultaneously assessed ligand-associated activity and downstream transcriptional output of the DLL4-NOTCH1 axis. We confirmed VEGF-induced target gene expression via Western blotting and quantitative real-time polymerase chain reaction. We further performed in vitro angiogenesis assays and in vivo Lewis lung carcinoma (LLC) allograft tumor experiments. Results: Among the 66 screened natural compounds, para-coumaric acid (p-CA) dose-dependently suppressed DLL4 transcription and NOTCH1 signaling activity in endothelial cells, with IC&lt;sub&gt;50&lt;\/sub&gt; values of 4.57 and 8.34 \u00b5&lt;sc&gt;m&lt;\/sc&gt;, respectively. Furthermore, p-CA significantly suppressed VEGF-induced endothelial cell proliferation, migration, and tube formation. In the LLC allograft model, p-CA treatment suppressed tumor growth and vascular density, increased pericyte coverage, reduced tumor hypoxia, and enhanced CD3+ T-cell infiltration and tumor cell apoptosis. Conclusion: In summary, p-CA is a natural compound that functionally suppresses VEGF-driven DLL4-NOTCH1 signaling in endothelial cells, exhibiting strong anti-angiogenic effects and promoting functional vascular normalization, resulting in marked tumor suppression and enhanced antitumor immunity in vivo. These findings suggest that p-CA warrants further investigation as an anti-angiogenic compound for cancer therapy.<\/jats:p>","DOI":"10.1159\/000553024","type":"journal-article","created":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T16:01:06Z","timestamp":1781884866000},"page":"105-118","source":"Crossref","is-referenced-by-count":0,"title":["Para-Coumaric Acid Suppresses Vascular Endothelial Growth Factor-Induced DLL4-NOTCH1 Signaling, Tumor Angiogenesis, and Tumor Growth"],"prefix":"10.1159","volume":"14","author":[{"given":"Seunghwan","family":"Ha","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jihye","family":"You","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"So Hee","family":"Bae","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyoung-Geun","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nam-In","family":"Baek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji-Hak","family":"Jeong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeong Ah","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"You Mie","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"127","published-online":{"date-parts":[[2026,6,19]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-023-01460-1"},{"key":"ref2","doi-asserted-by":"publisher","DOI":"10.1007\/s12272-020-01287-2"},{"key":"ref3","doi-asserted-by":"publisher","DOI":"10.1007\/s12272-022-01389-z"},{"key":"ref4","doi-asserted-by":"publisher","DOI":"10.1097\/MOH.0b013e32833865b9"},{"key":"ref5","doi-asserted-by":"publisher","DOI":"10.1007\/s12272-023-01454-1"},{"key":"ref6","doi-asserted-by":"publisher","DOI":"10.1016\/s0008-6363(00)00281-9"},{"key":"ref7","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.109.185165"},{"key":"ref8","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.642352"},{"key":"ref9","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2009.05.019"},{"key":"ref10","doi-asserted-by":"publisher","DOI":"10.3892\/or.2018.6427"},{"key":"ref11","doi-asserted-by":"publisher","DOI":"10.1038\/nature05355"},{"key":"ref12","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2024-009636"},{"key":"ref13","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2025.123412"},{"key":"ref14","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-22-0243"},{"key":"ref15","doi-asserted-by":"publisher","DOI":"10.5483\/BMBRep.2020.53.10.103"},{"key":"ref16","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2012.01.033"},{"key":"ref17","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2007.08.006"},{"key":"ref18","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-12-0640"},{"key":"ref19","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-15-1380"},{"key":"ref20","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2022.154513"},{"key":"ref21","doi-asserted-by":"publisher","DOI":"10.3390\/ijms27031576"},{"key":"ref22","doi-asserted-by":"publisher","DOI":"10.1007\/s12272-025-01539-z"},{"key":"ref23","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M107234200"},{"key":"ref24","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2020.153318"},{"key":"ref25","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.06.054"},{"key":"ref26","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a006569"},{"key":"ref27","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1998.9719"},{"key":"ref28","doi-asserted-by":"publisher","DOI":"10.1159\/000538271"},{"key":"ref29","doi-asserted-by":"publisher","DOI":"10.1016\/s1535-6108(03)00168-5"},{"key":"ref30","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0308075"},{"key":"ref31","doi-asserted-by":"publisher","DOI":"10.1007\/s10555-007-9094-7"},{"key":"ref32","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-08-3779"},{"key":"ref33","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-16-0365"},{"key":"ref34","doi-asserted-by":"publisher","DOI":"10.1038\/nri3839"},{"key":"ref35","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.23.1.14-25.2003"},{"key":"ref36","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-020-00952-9"},{"key":"ref37","doi-asserted-by":"publisher","DOI":"10.1038\/nm0901-987"},{"key":"ref38","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-023-02148-7"},{"key":"ref39","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.3625"},{"key":"ref40","doi-asserted-by":"publisher","DOI":"10.1039\/d4cp03575e"},{"key":"ref41","doi-asserted-by":"publisher","DOI":"10.1007\/s12032-025-02792-4"}],"container-title":["Pulse"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/karger.com\/article-pdf\/doi\/10.1159\/000553024","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T16:01:04Z","timestamp":1785945664000},"score":1,"resource":{"primary":{"URL":"https:\/\/karger.com\/article\/doi\/10.1159\/000553024"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,19]]},"references-count":41,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1,1]]}},"URL":"https:\/\/doi.org\/10.1159\/000553024","archive":["Portico"],"relation":{"is-supplemented-by":[{"id-type":"doi","id":"10.6084\/m9.figshare.32740740","asserted-by":"subject"}]},"ISSN":["2235-8676","2235-8668"],"issn-type":[{"value":"2235-8676","type":"print"},{"value":"2235-8668","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,19]]}}}