Scutellarin suppresses triple-negative breast cancer metastasis by inhibiting TNFα-induced vascular endothelial barrier breakdown

• Published in: Acta pharmacologica Sinica 2022-10, Vol.43 (10), p.2666-2677
• Main Authors: Mei, Xi-yu, Zhang, Jing-nan, Jia, Wang-ya, Lu, Bin, Wang, Meng-na, Zhang, Tian-yu, Ji, Li-li
• Format: Article
• Language: English
• Subjects: Apigenin - pharmacology; Biomedical and Life Sciences; Biomedicine; Breast cancer; Cell Line, Tumor; Cell migration; Endothelial cells; Extracellular signal-regulated kinase; Flavonoids; Glucuronates; Human Umbilical Vein Endothelial Cells - metabolism; Humans; Immunology; Internal Medicine; Kinases; Medical Microbiology; Metastases; Metastasis; Microvasculature; Nuclear transport; Pharmacology/Toxicology; Protein kinase; Protein Kinases; Receptors, Tumor Necrosis Factor, Type II; Signal transduction; Triple Negative Breast Neoplasms - pathology; Tumor necrosis factor receptors; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-TNF; Tumor necrosis factor-α; Umbilical vein; Vaccine
• ISSN: 1671-4083; 1745-7254; 1745-7254
• DOI: 10.1038/s41401-022-00873-y

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with high vascularity and frequent metastasis. Tumor-associated abnormal vasculature was reported to accelerate TNBC metastasis. Scutellarin (SC) is a natural flavonoid with a cardiovascular protective function. In this study, SC reduced TNBC metastasis and alleviated tumor-associated vascular endothelial barrier injury in vivo. SC rescued the tumor necrosis factor-α (TNFα)-induced diminishment of endothelial junctional proteins and dysfunction of the endothelial barrier in vitro. SC reduced the increased transendothelial migration of TNBC cells through a monolayer composed of TNFα-stimulated human mammary microvascular endothelial cells (HMMECs) or human umbilical vein endothelial cells (HUVECs). TNFα induced the nuclear translocation of enhancer of zeste homolog-2 (EZH2), and its chemical inhibitor GSK126 blocked TNFα-induced endothelial barrier disruption and subsequent TNBC transendothelial migration. TNF receptor 2 (TNFR2) is the main receptor by which TNFα regulates endothelial barrier breakdown. Extracellular signal-regulated protein kinase (ERK)1/2 was found to be downstream of TNFα/TNFR2 and upstream of EZH2. Additionally, SC abrogated the TNFR2-ERK1/2-EZH2 signaling axis both in vivo and in vitro. Our results suggest that SC reduced TNBC metastasis by suppressing TNFα-initiated vascular endothelial barrier breakdown through rescuing the reduced expression of junctional proteins by regulating the TNFR2-ERK1/2-EZH2 signaling pathway.