Phomaketide A Inhibits Lymphangiogenesis in Human Lymphatic Endothelial Cells

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Title:	Phomaketide A Inhibits Lymphangiogenesis in Human Lymphatic Endothelial Cells
Authors:	Huai-Ching, T;Tai, Huai-Ching;Tzong-Huei, L;Lee, Tzong-Huei;湯智昕;Chih-Hsin;Tang;Chen, Lei-Po;Chen, Lei-Po;Ch, Wei-Cheng;Chen, Wei-Cheng;Ming-Shian, L;Lee, Ming-Shian;Chen, Pei-Chi;Chen, Pei-Chi;Li, Chih-Yang;Lin, Chih-Yang;Chi, Chih-Wen;Chi, Chih-Wen;Chen, Yu-Jen;Chen, Yu-Jen
Contributors:	生物科技學系
Date:	2019-04
Issue Date:	2019-11-08 02:56:46 (UTC+0)
Abstract:	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 Cδ (PKCδ), 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, PKCδ, 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.
Relation:	Marine Drugs
Appears in Collections:	[Department of Biotechnology] Journal Article

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