Zoledronic Acid Inhibits Angiogenesis Through Promoting HIF-1 alpha Protein Degradation in Human Umbilical Vein Endothelial Cells

摘要

Zoledronic acid (ZOL) is the third generation nitrogen containing bisphosphonate widely used for the treatment of cancer-induced bone diseases. Prior studies showed that ZOL reduced the number of endothelial cells and subsequently inhibited angiogenesis after tooth extraction, leading to bisphosphonates-induced osteonecrosis of the jaw (BP-ONJ). However, its underlying molecular mechanisms are still unclear. Our results showed that ZOL concentration-dependently inhibited cell viability, migration, adhesion and tube formation by decreasing vascular endothelial growth factor (VEGF) expression and secretion. In addition, ZOL decreased HIF-1 alpha protein level, but had no effect on HIF-1 alpha mRNA level and promoter activity. Mechanically, we found that ZOL attenuated HIF-1 alpha protein stability through attenuating the activation of PI3K/AKT/mTOR and MAP kinase pathways. Moreover, ZOL impaired HIF-1 alpha/Hsp90 and HIF-1 alpha/p300 interactions, which are responsible for HIF-1 alpha destabilization. Overexpression of Hsp90 or p300 with adenovirus significantly inhibited ZOL-induced the decrease of HIF-1 alpha and VEGF protein expression. Collectively, our data demonstrate that ZOL exhibits an antiangiogenic effect via inhibition of HIF-1 alpha-dependent VEGF expression and secretion, which is due to destabilization of HIF-1 alpha protein.