Abstract
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.
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Acknowledgements
The authors thank Prof. Zi-jia Zhang (Shanghai University of Traditional Chinese Medicine, Shanghai) for kindly gifting MDA-MB-231 cells. This work was financially supported by National Natural Science Foundation of China (82074084) and the leadership in Science and Technology innovation of the third batch of national “Ten Thousand People Plan” for LLJ.
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XYM and LLJ conceived and designed the study; XYM, JNZ, WYJ, MHW, TYZ, and BL performed the experiments and analyzed the data; XYM drafted the manuscript; LLJ reviewed and edited the manuscript.
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Mei, Xy., Zhang, Jn., Jia, Wy. et al. Scutellarin suppresses triple-negative breast cancer metastasis by inhibiting TNFα-induced vascular endothelial barrier breakdown. Acta Pharmacol Sin 43, 2666–2677 (2022). https://doi.org/10.1038/s41401-022-00873-y
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DOI: https://doi.org/10.1038/s41401-022-00873-y
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