| Summary: | 碩士 === 國立陽明大學 === 生理學研究所 === 98 === Breast cancer is the most frequent cause of mortality among females in the world. The death reasons of most breast cancer patients were due to the tumor metastasis from breast to other organs. The principal mechanisms involved in metastasis are migration and invasion. Unfortunately, there are almost no efficacious therapeutic modalities. Thus, it is imperative to develop novel targets and agents to prevent invasion and metastasis of breast cancer cells. Isoliquiritigenin (ISL) is natural phenolic compound extracts from licorice. Previous studies have shown that ISL is a potent antioxidant with anti-inflammatory and antitumor activities. Vascular endothelial growth factor (VEGF), a pivotal stimulator of angiogenesis, promotes endothelial migration and tumor growth. Matrix metalloproteinases (MMPs), one class of proteolytic enzymes, can degrade the extraceullar matrix (ECM) and enable tumor cells to invasion. Both VEGF and MMPs play important roles in tumor invasion and metastasis. This purpose of this study is to investigate the anti-metastatic potency of ISL via modulation of the expression of VEGF and MMP in the highly metastatic human breast cancer cell line MDA-MB-231. Based on ELISA and western blot analysis, ISL treatment (0.1-10 μΜ) for 24 h and 48 h reduced secretions and protein levels of VEGF in a time- and dose-dependent manner. ISL decreased the hypoxia-inducible factor 1-alpha (HIF-1α) protein expression, which is the up-regulator of VEGF. According to chamber migration assay and wound migration assay, ISL significantly suppressed the migration of MDA-MB-231 cells at 24 h and 48 h. Among human MMPs, MMP-2 and MMP-9 have been of particular interest because they efficiently cleave the major components of ECM. As confirmed by western blot and gelatin zymography assay, ISL inhibited the protein expression and gelatinolytic activity of MMP-2/-9 at 48 h. To further clarify the signal pathway responsible for ISL-downregulated cell migration in MDA-MB-231 cells, we examine the effect of ISL on PI3K/Akt pathway and MAPK pathway, as well as the NF-κB. The expression of PI3K and phosphorylation of p38 mitogen-activated protein kinase and Akt kinase were suppressed after ISL treatment. In addition, NF-κB DNA binding assay demonstrated that NF-κB DNA binding activity was inhibited after ISL treatment. Taken together, these findings suggest that ISL inhibits p38, PI3K/Akt, and NF-κB signaling, resulting in the inhibition of VEGF, HIF-1α, MMP-9, and MMP-2, and thus suppresses migration of MDA-MB-231 cells. We believe that these findings will provide the potential application of ISL on the treatment of metastatic breast cancer.
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