Antiangiogenic activity of isoliquiritigenin through down-regulation of vascular endothelial growth factor and its receptors expression

4801

Breast cancer, as with most solid tumors, needs to develop the angiogenic phenotype for invasiveness, progression and metastasis. Angiogenesis is regulated by a network of inducing and inhibiting factors under physiologic conditions, whereas in pathologic conditions, such regulation is altered or absent. A number of pro-angiogenic factors have been identified, the most potent of which is vascular endothelial growth factor (VEGF)/vascular permeability factor (VPF). VEGF is an intensively studied molecule that has significant potential, both in stimulating angiogenesis and as a target for antiangiogenic approaches. VEGF has an influence on the proliferation as well as migration in breast cancer and endothelial cells. It has also been shown to act as a survival factor for metastatic breast cancer cells. Reduced VEGF expression relates with decreased survival of breast cancer cells and induction of apoptosis. VEGF achieves its multiple functions by activating two receptor tyrosine kinases, Flt-1 (VEGF receptor-1) and KDR (VEGF receptor-2), both of which are selectively expressed on primary vascular endothelium. The interaction of VEGF and its receptors regulates tumor angiogenesis. Therefore, blocking the binding of VEGF and the corresponding receptor has become critical for anti-angiogenesis therapy. In the current study, we found that isoliquiritigenin (ISL) reduced protein expression of VEGF and its receptors as well as mRNA level in both human breast cancer cells, estrogen receptor positive MCF-7 and estrogen receptor negative MDA-MB-231 cells. ISL also inhibited dose- and time- dependently the proliferation of breast cancer cells in the presence and absence of VEGF. Moreover, ISL suppressed VEGF-induced cell proliferation, tube formation and cell migration in human umbilical vein endothelial cells (HUVECs). Antiangiogenic activity of ISL was confirmed in mouse Matrigel plug assay. Finally, we examined the effect of ISL on focal adhension kinase (FAK)-mediated signaling, which is closely associated with cellular functions, such as cell adhension, spreading and motility, in HUVECs. In conclusion, these results suggest that inhibition of VEGF expression can be one of the molecular mechanisms involved in the antiangiogenic effects of ISL, which may contribute to its potential use for breast cancer treatment and/or prevention.