Hepatocyte growth factor (HGF) and its receptor, Met, known to control invasive growth program have recently been shown to play crucial roles in the survival of breast cancer patients. Apigenin, a common dietary flavonoid, has been found to have anti-tumor properties and therefore poses special interest for the development of chemopreventive and/or chemotherapeutic agent for cancers; however, knowledge on the pharmacological and molecular mechanisms in suppressing HGF/Met-mediated tumor invasion and metastasis is poorly understood. In our preliminary study, we use HGF as an invasive inducer to investigate the effect of apigenin on HGF-dependent invasive growth of MDA-MB-231 human breast cancer cells. Here we demonstrate that apigenin represses the HGF-induced cell migration and invasion in a dose-dependent manner. The effect of apigenin on HGF-induced signaling activation involving invasive growth was evaluated by immunoblotting analysis, it shows that apigenin blocks the HGF-induced Akt phosphorylation but not Met, ERK, and JNK phosphorylation. By immunofluorescence microscopy assay, apigenin inhibits the HGF-induced clustering of beta 4 integrin through PI3K-dependent manner which suppress HGF-stimulated integrin beta 4 function including cell-matrix adhesion and cell-endothelial cells adhesion in MDA-MB-231 cells. By Akt-siRNA transfection analysis, it confirmed that apigenin inhibited HGF-promoted invasive growth involving blocking PI3K/Akt pathway. Finally, we evaluated the effect of apigenin on HGF-promoted metastasis by lung colonization in nude mice and organ metastasis in chick embryo. Histological and gross examination of mouse lung and real-time PCR analysis of human alu in host tissues, it showed that apigenin inhibit HGF-promoted metastasis. These data support the inhibitory effect of apigenin on HGF-promoted invasive growth and metastasis involving blocking PI3K/Akt pathway and integrin beta 4 function and it might be a useful agent for chemoprevention and/or chemotherapeutics of breast cancers.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3089.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

American Association for Cancer Research
2009