The protein biosynthesis inhibitor vioprolide A evokes anti-angiogenic and pro-survival actions by targeting NOP14 and decreasing VEGF receptor 2- and TAZ-signaling

Biomedicine & Pharmacotherapy

Rolf Müller¹  Stylianos Michalakis²  Yanfen Li²  Stefan Zahler³  Luisa D. Burgers⁴  Sarah Ciurus⁴  Robert Fürst⁴ 

[1] Department of Microbial Natural Products, Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Center for Infection Research and Department of Pharmacy at Saarland University, Saarbrücken, Germany;Department of Ophthalmology, University Hospital, LMU Munich, Germany;Department of Pharmacy – Center for Drug Research, Pharmaceutical Biology, LMU Munich, Germany;Institute of Pharmaceutical Biology, Faculty of Biochemistry, Chemistry and Pharmacy, Goethe University, Frankfurt, Germany;

关键词: Vioprolide A;    Endothelial cells;    Protein biosynthesis;    Angiogenesis;    Angiogenesis-related cell functions;    VEGF receptor 2;   

DOI  :  

来源: DOAJ

【 摘 要 】

Angiogenesis contributes to the progression of several diseases including cancer or age-related macular degeneration and is crucially driven by pathologically hyperactive endothelial cells (ECs). Targeting angiogenic processes in ECs thus represents a promising strategy to treat these conditions. Vioprolide A (vioA) is a myxobacterial cyclic depsipeptide that targets the nucleolar protein 14 (NOP14) and possesses strong anti-cancer and anti-inflammatory actions. Here, we present evidence that vioA promotes anti-angiogenic actions in vivo and in ECs in vitro. VioA reduced the choroidal neovascularization after laser-induced photocoagulation in mice in vivo, the sprouting of choroidal explant cultures ex vivo and key angiogenic features of ECs in vitro. Mechanistically, vioA decreased VEGFR2 protein levels and phosphorylation leading to impaired downstream pro-angiogenic signaling. Concurrently, vioA influenced TAZ signaling by diminishing its nuclear translocation and protein level, resulting in a reduced expression of pro-angiogenic target genes and dynamic cytoskeletal remodeling. Surprisingly, vioA induced pro-survival signaling in ECs by activating Akt and inhibiting p53-dependent apoptosis. Knockdown of the cellular target NOP14 further revealed a partial involvement in the anti-angiogenic and pro-survival actions of vioA. Taken together, our study introduces vioA as an interesting anti-angiogenic compound that warrants further investigations in preclinical studies.

【 授权许可】

Unknown