Phomaketide A Inhibits Lymphangiogenesis in Human Lymphatic Endothelial Cells.

Huai-Ching Tai,Ming-Shian Lee,Chih-Wen Chi,Shiou-Sheng Chen,Kuang-Wen Liao,Cheng-Ta Lai,Lei-Po Chen,Wei-Cheng Chen,Chih-Yang Lin,Shih-Wei Wang,Chien-Hsing Lee,Chih-Hsin Tang,Tzong-Huei Lee,Yu-Jen Chen,Pei-Chi Chen

doi:10.3390/md17040215

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.

Highlights

Cancer metastasis enables cancer cells to spread from the primary tumor and establish themselves in other tissues
Since the migratory ability of endothelial cells is another essential characteristic of lymphangiogenesis [15], we evaluated the effect of phomaketide A on lymphatic endothelial cells (LECs) migration
To elucidate the mechanisms employed by phomaketide A to regulate lymphangiogenesis, we explored its effects upon vascular endothelial growth factor receptor-3 (VEGFR-3) in LECs

Summary

Introduction

Cancer metastasis enables cancer cells to spread from the primary tumor and establish themselves in other tissues. Lymphatic circulation is a common route for cancer metastasis [1], with the thin walls and few tight junctions in the lymphatic vessels offering good permeability. The lack of basal lamina and associated pericytes, means that lymphatic capillaries have an easy opening for the uptake of macromolecular cancer cells into the lymphatic vessels [2,3]. Lymphangiogenesis, the process by which new lymphatic vessels grow out of pre-existing vessels, enables lymphatic endothelial cells (LECs) to proliferate and migrate through lymphatic vessels surrounding the tumors [4,5]. LEC survival, proliferation, migration and tube formation depends upon the activation of the VEGF-C/VEGFR-3 axis [9]

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Results

Conclusion