biostudies-literature00440Unknown17(4)Tai HCMackay Memorial HospitalMinistry of Science and Technology, TaiwanTaipei City HospitalMackay Medical CollegeLymphangiogenesis 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 <i>Phoma</i> 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 <i>in vitro</i> and <i>in vivo</i>, which suggests that this natural product could potentially treat cancer metastasis.Marine drugshttps://www.ebi.ac.uk/biostudies/studies/S-EPMC6520718biostudies-literaturePhomaketide A Inhibits Lymphangiogenesis in Human Lymphatic Endothelial Cells.PMC6520718MMH-108-94MOST 106-2320-B-715-001-MY3; MOST 107-2320-B-030-005MMC-1071B27TCH 10701-62-027Wang SWTai HCChen WCLee THChen SSLai CTChen LPChi CWLin CYTang CHLiao KWLee MSLee CHChen YJChen PC44falsePhomaketide A Inhibits Lymphangiogenesis in Human Lymphatic Endothelial Cells.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 <i>Phoma</i> 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 <i>in vitro</i> and <i>in vivo</i>, which suggests that this natural product could potentially treat cancer metastasis.2019-01-01T00:00:00Z2019 Apr2021-03-11T08:25:01Z2019-07-01T13:52:17ZS-EPMC65207183095990710.3390/md17040215