RESUMEN
Liquiritigenin (LQ) is a non-toxic dietary flavonoid with chemopreventive and anticancer properties. However, the mechanism of its antiangiogenesis remains unclear. Hypoxia-inducible factor-1α (HIF-1α) and its downstream target, vascular endothelial growth factor (VEGF), play a critical role in tumour angiogenesis and represent an attractive chemotherapeutic target. In this study, we investigated the effect of LQ on the molecular mechanism of angiogenesis. We found that LQ inhibited VEGF expression at both mRNA and protein levels. Liquiritigenin did not affect HIF-1α expression at the mRNA level, but it dramatically inhibited both serum- and mimicked hypoxic-induced HIF-1α protein accumulation in HeLa cells. Furthermore, we showed that LQ inhibited serum-induced expression of HIF-1α by reducing its stability and decreased the synthesis in a dose-dependent manner. Mechanistically, we demonstrated that LQ inhibited HIF-1α and VEGF expression involved in blocking the protein kinase B (PKB/Akt) signalling pathway, and the mechanisms correlated with dephosphorylation of the mammalian target of rapamycin (mTOR) and its effector ribosomal protein S6 kinase (p70S6K). In addition, LQ inhibited VEGF-induced formation of capillary-like structures in human umbilical vein endothelial cells (HUVEC). Taken together, our study provided valuable insights into the mechanism of antiangiogenic effect of LQ.
Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Flavanonas/farmacología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Transducción de Señal , Factor A de Crecimiento Endotelial Vascular/metabolismo , Relación Dosis-Respuesta a Droga , Células HeLa , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación , Biosíntesis de Proteínas/efectos de los fármacos , Estabilidad Proteica , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas Quinasas S6 Ribosómicas 70-kDa/genética , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Suero/metabolismo , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Activación Transcripcional , Factor A de Crecimiento Endotelial Vascular/genéticaRESUMEN
It has been demonstrated that many flavonoids possess a potent and broad spectrum of antitumor activity. Liquiritigenin is a flavanone extracted from Glycyrrhizae. This study investigated the effects of liquiritigenin on cell viability and apoptosis induction in human cervical carcinoma (HeLa) cells. The results show that liquiritigenin significantly suppressed cell proliferation in a dose- and time-dependent manner in HeLa cells. In addition, liquiritigenin promoted apoptosis in HeLa cells, evidenced by apoptotic morphological changes and Annexin-V binding. The apoptosis induction with liquiritigenin is associated with the up-regulation of p53 and Bax, along with down-regulation of Bcl-2 and survivin. Finally, examination of the mitochondrial pathway of apoptosis revealed that cytochrome c is released from mitochondria to cytosol, associated with the activation of caspase-9 and -3, and the cleavage of poly (ADP-ribose) polymerase (PARP). Overall, the results indicate that liquiritigenin induces apoptosis in part via the mitochondrial pathway, which is associated with p53 up-regulation, release of cytochrome c and elevated activity of caspase-9 and -3 in HeLa cells.