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 IC50 values of 4.57 and 8.34 µm, 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.
| Mualliflar | 하승환, Jihye You, So Hee Bae, Hyoung-Geun Kim, Nam‐In Baek, Ji-Hak Jeong, Jeong Ah Kim, You Mie Lee |
|---|---|
| Jurnal | PULSE |
| Nashr sanasi | 2026-06-19 |
| Jild | 14 |
| Son | 1 |
| Betlar | 105-118 |
| Til | en |
| DOI | 10.1159/000553024 |
DOI: 10.1159/000553024 · Maqolaning asl sahifasi · PDF
Introduction: Arterial stiffness, measured by brachial-ankle pulse wave velocity (baPWV), has been linked to diabetic peripheral neuropathy (DPN). However, the evidence regarding its association with large-nerve fiber…
Introduction: The cardio-ankle vascular index (CAVI) is a noninvasive indicator used to assess arterial stiffness and predict atherosclerotic cardiovascular disease (ASCVD). CAVI represents a scale-converted form of the…
Methods and techniques for assessing out-of-office blood pressure (20'+5')
Introduction: Whole blood donation is generally considered to be a safe procedure, but occasionally adverse reactions of varying severity may occur during or at the end of the collection. The aim of this study is to…
In an ageing population, degenerative aortic stenosis (AS) and elevated arterial stiffness frequently coexist, imposing a combined valvular and pulsatile arterial afterload on the left ventricle (LV). Since the…
Background: Anaemia is a serious public health concern all over the world. It is a huge health burden for low and middle-income countries. Reproductive-age women, especially pregnant women, suffer a lot due to this…
Introduction: Although "Life’s Essential 8" (LE8) is a key metric for cardiovascular health (CVH), its longitudinal association with subclinical atherosclerosis in Koreans remains unclear. We examined the association…
Background: Peritoneal inflammatory nodules are rare, non-neoplastic lesions that can be associated with endometrioid carcinoma of the uterus. Grossly, these lesions may closely resemble peritoneal carcinomatosis…
Background: Carotid body tumors (CBTs) are rare, highly vascular neuroendocrine tumors originating from paraganglionic cells in the carotid bifurcation. Case Presentation: We report the case of a 21-years-young female…
Laryngeal cancer is the second most common type of head & neck malignancies. This cancer commonly spreads to regional lymph nodes and distant metastasis is rare. Liver metastasis rarely occurs without evidence of lung…