Phomaketide A inhibits lymphangiogenesis in human lymphatic endothelial cells

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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 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.

Original languageEnglish
Article number215
JournalMarine Drugs
Volume17
Issue number4
DOIs
StatePublished - 1 Jan 2019

Keywords

  • Lymphangiogenesis
  • Lymphatic endothelial cells
  • Phomaketide a
  • Vascular endothelial growth factor receptor-3

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