Anti-angiogenesis Effects of Borrelidin are Mediated through Distinct Pathways: Threonyl-tRNA Synthetase and Caspases are Independently Involved in Suppression of Proliferation and Induction of Apoptosis in Endothelial Cells

Borrelidin, an antibiotic with anti-angiogenic activity, not only suppresses new capillary tube formation, but also collapses formed capillary tubes in a rat aorta culture model. Since it selectively inhibits threonyl-tRNA synthetase, we examined the effect of threonine on its anti-angiogenic activity. We found that a high concentration of threonine (1 mM) attenuated the ability of borrelidin to inhibit both capillary tube formation in the rat aorta culture model and human umbilical vein endothelial cells (HUVEC) proliferation, yet did not affect the ability of borrelidin to collapse formed capillary tubes or to induce apoptosis in HUVEC. Borrelidin activated caspase-3 and -8, and inhibitors of both caspase-3 and -8 suppressed borrelidin-induced apoptosis in HUVEC. Taken together, these data suggest that the anti-angiogenic effects of borrelidin are mediated through at least two mechanisms, i.e. one threonine-dependent and the other threonine-independent, and borrelidin induces apoptosis in endothelial cells via the caspase-8/-3 pathway.