標題: Phomaketide A Inhibits Lymphangiogenesis in Human Lymphatic Endothelial Cells
作者: Tai, Huai-Ching
Lee, Tzong-Huei
Tang, Chih-Hsin
Chen, Lei-Po
Chen, Wei-Cheng
Lee, Ming-Shian
Chen, Pei-Chi
Lin, Chih-Yang
Chi, Chih-Wen
Chen, Yu-Jen
Lai, Cheng-Ta
Chen, Shiou-Sheng
Liao, Kuang-Wen
Lee, Chien-Hsing
Wang, Shih-Wei
交大名義發表
分子醫學與生物工程研究所
National Chiao Tung University
Institute of Molecular Medicine and Bioengineering
關鍵字: phomaketide A;lymphangiogenesis;lymphatic endothelial cells;vascular endothelial growth factor receptor-3
公開日期: 1-四月-2019
摘要: Lymphangiogenesis is an important biological process associated with cancer metastasis. The development of new drugs that block lymphangiogenesis represents a promising therapeutic strategy. Marine fungus-derived compound phomaketide A, isolated from the fermented broth of Phoma sp. NTOU4195, has been reported to exhibit anti-angiogenic and anti-inflammatory effects. However, its anti-lymphangiogenic activity has not been clarified to date. In this study, we showed that phomaketide A inhibited cell growth, migration, and tube formation of lymphatic endothelial cells (LECs) without an evidence of cytotoxicity. Mechanistic investigations revealed that phomaketide A reduced LECs-induced lymphangiogenesis via vascular endothelial growth factor receptor-3 (VEGFR-3), protein kinase C (PKC), and endothelial nitric oxide synthase (eNOS) signalings. Furthermore, human proteome array analysis indicated that phomaketide A significantly enhanced the protein levels of various protease inhibitors, including cystatin A, serpin B6, tissue factor pathway inhibitor (TFPI), and tissue inhibitor matrix metalloproteinase 1 (TIMP-1). Importantly, phomaketide A impeded tumor growth and lymphangiogenesis by decreasing the expression of LYVE-1, a specific marker for lymphatic vessels, in tumor xenograft animal model. These results suggest that phomaketide A may impair lymphangiogenesis by suppressing VEGFR-3, PKC, and eNOS signaling cascades, while simultaneously activating protease inhibitors in human LECs. We document for the first time that phomaketide A inhibits lymphangiogenesis both in vitro and in vivo, which suggests that this natural product could potentially treat cancer metastasis.
URI: http://dx.doi.org/10.3390/md17040215
http://hdl.handle.net/11536/151969
ISSN: 1660-3397
DOI: 10.3390/md17040215
期刊: MARINE DRUGS
Volume: 17
Issue: 4
起始頁: 0
結束頁: 0
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