Apigenin Regulates Matrix Metalloproteinase-2/9 and Rho gtpase family through fAk signal to reduce Breast Cancer MCf-7 cells Metastasis

Cancer metastasis is the toughest problem in cancer therapy. once tumor cells have the ability of surrounding cell invasion, the survival rate of patient with tumor disease will be reduced. hence, prevent or reduce the cancer metastasis will can increase the patients’ survival rate. Apigenin has been demonstrated optimal effect in cancer prevention and reduce cancer metastasis, including breast cancer. In this study, we verify low dose (≦5 μg/ml) apigenin exposure 3 h would not influence the MCF-7 cells viability but can decrease its fAk signal activation to reduce matrix metalloproteinases (MMp-2 and MMp-9) expression. Moreover, low dose apigenin treated in MCf-7 cells could reduce the cell mobility through the Rho gtpases (Ras, Rac-1, cdc-42, and RhoA) downregulation to cause cytoskeleton remodeling. presented results have demonstrated the role of apigenin on breast cancer metastasis is associated with fAk signal pathway inhibition. The capacity of low dose apigenin treated in breast cancer for short time has been clarified here. And thus may find widespread application in clinical therapy as an anti-metastatic medicament. keywords: Cancer metastasis,Apigenin,Matrix metalloproteinases,Rho gtpases Introduction Breast cancer is the common cancer of women and the ranking 5th leading cause of death worldwide [1]. the risk factor of breast cancer development including, obesity, drinking alcohol, early age at first menstruation, having children late or not at all, older age, etc. About 5–10% of cases are genomic alteration, including BRCA1 and BRCA2 mutation [2]. Surgery is the major method to remove the tumor. Chemotherapy, radiation therapy and hormone therapy are often used to reduce the recurrence. the majority of early-stage breast cancer patients was undergo breast conserving surgery and then receive adjuvant treatment. the 5-years survival of early-stage breast cancer is 98.6%. While in late-stage, often associated with metastasis, these therapies could not achieve the optimal treatment and cause the survival rate declines to 24.3% [3]. furthermore, once breast cancer with metastasis will cause poor outcome. therefore, inhibition of breast cancer metastasis can extend the patients’ survival. Cancer metastasis is a complex process, the local tumor cells migrate to distant site by the bloodstream, the lymphatic system, or by direct extension. Among them, the epithelial-mesenchymal transition (EMt) is the important characteristics. EMt is the conserved developmental process in the evolution [4], and it also plays pivotal role in cancer metastasis. Cytokines and growth factors, such as transforming growth factor β (TGF-β) are related with EMt dysregulation during the process of malignant tumor [5]. In the EMt process, the cell-cell junction would be breakdown by E-cadherin reducing, and the Rho gtpase function also be modulated, loss of cell polarity ensues, a dramatic reorganization of the actin cytoskeleton to enhance cell motile characteristics [5-7]. once cancer metastasis, the survival rate of cancer patients would be reduced. But, the molecular mechanism of cancer metastasis happen is unclear. therefore, in clinical, inhibition of cancer metastasis is the crucial issues to prolong the life of tumor diseases patients. Apigenin (4’,5,7-trihydroxyflavone) is a plants source natural product, belonging to the flavone class. The functions of apigenin are recognized as anti-inflammatory, antioxidant and anticancer. Apigenin has been shown effective in inhibiting several cancers, including breast cancer [8], lung cancer [9], oral cancer [10], gastric cancer [11], colon cancer [12], bladder cancer [13],