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Chemical biology analysis of borrelidin identifies an essential translational enzyme as a pro‐angiogenic modulator of tumor progression in multiple human cancers
Author(s) -
Francklyn Christopher S.,
Lounsbury Karen,
Williams Tamara,
Mirando Adam
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.805.7
Subject(s) - angiogenesis , vascular endothelial growth factor , biology , cancer research , cell culture , metastasis , cell , cancer , microbiology and biotechnology , chemistry , biochemistry , vegf receptors , genetics
Phenotypic screening is a valuable tool in the discovery of new cancer therapeutics. Borrelidin, an 18‐carbon macrolide antibiotic produced by Streptomyces, inhibits the protein synthesis enzyme threonyl‐tRNA synthetase (TARS), while also blocking angiogenesis in cell culture and metastasis in a mouse model of melanoma. To explain the molecular basis of the effect of borrelidin and its less toxic derivative BC‐194 on angiogenesis, we examined the response of 80 different angiogenesis specific genes in SKOV cells to macrolide. Borrelidin and BC‐194 altered the expression of vascular endothelial growth factor (VEGF) and protein levels of HIF‐1, the hypoxia inducible factor that controls VEGF synthesis. TARS was revealed by the human vein endothelial cell (HUVEC) tube formation and chick chorionic allantoic membrane (CAM) assays to be a pro‐angiogenic factor with a potency rivaling VEGF and basic‐FGF. BC‐194 blocked these pro‐angiogenic functions. TNF‐alpha and VEGF stimulated TARS secretion from HUVECs, and TARS promoted angiogenesis by stimulating cell migration. The clinical significance of these observations is suggested by the involvement of TARS in selected human autoimmune diseases, and by its statistically significant expression increases in tissue samples from ovarian and prostate cancer patients. Supported by NIGMS and the Lake Champlain Regional Cancer Organization