Mechanistic Study Of The Integrin β CT-derived Antiangiogenic Peptides

Angiogenesis is essentially required to support solid tumor growth, and therefore antiangiogenic strategies have become attractive therapeutic options for malignant tumor. Integrins are α/β heterodimeric cell adhesion receptors and integrin members expressed in vascular endothelial cells play important roles in promoting angiogenesis. The functions of integrin are tightly regulated by the α/β cytoplasmic tails(CTs); however, how the integrin CTs, especially the conserved regions in the βCT, influence angiogenesis is largely unknown. In this study, we employed a series of membrane-permeable integrin βCT-derived peptides(mβCTPs) and evaluated their antiangiogenic effects. By performing HUVEC tube formation assays, we found that the mβCTPs derived from β3CT, β5CT and β6CT exhibited significant antiangiogenic activity. Interestingly, we identified β3-endonexin, a nuclear protein with a typical nuclear localization sequence(NLS), as a common binding protein for the antiangiogenic mβCTPs. Further functional analyses showed that down- and up-regulations of β3-endonexin in HUVECs respectively suppressed and promoted tube formation; however, up-regulation of β3-endonexin carrying a defective NLS in HUVECs had no effect on tube formation, suggesting that nuclear localization of β3-endonexin may act as a proangiogenic factor. Significantly, we found that the antiangiogenic mβCTPs had the ability to inhibit nuclear localization of β3-endonexin in HUVECs, which provides a mechanistic explanation for the antiangiogenic feature of mβCTPs. Taken together, we identify a novel antiangiogenic strategy by targeting β3-endonexin with the mβCTPs, which presents an attractive option for developing the next-generation antiangiogenic drugs.