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  • Title: Phloretin suppresses metastasis by targeting protease and inhibits cancer stemness and angiogenesis in human cervical cancer cells.
    Author: Hsiao YH, Hsieh MJ, Yang SF, Chen SP, Tsai WC, Chen PN.
    Journal: Phytomedicine; 2019 Sep; 62():152964. PubMed ID: 31153059.
    Abstract:
    BACKGROUND: Phloretin, a dihydrochalcone flavonoid, possesses anti-inflammatory activity and inhibits the growth of various cancers. However, the flavonoid's effect on cervical cancer metastasis and angiogenesis remains unknown. PURPOSE: In this study, we provide molecular evidence associated with the antimetastatic and antiangiogenic effects of phloretin. METHODS: In this study, the anti-invasive effect of phloretin (0-60 μM) in cervical cancer cells was evaluated using the Matrigel invasion assay, gelatin zymography, cell-matrix adhesion assay, wound healing assay, and Western blotting. Antiangiogenic potential of phloretin (0-100 μM) was assessed by the Matrigel tube formation assay. The in vivo antitumor effect of phloretin (10 or 20 mg/kg) was fed by oral gavage and determined using subcutaneous inoculation and tail vein injection in immunodeficient nude mice. RESULTS: Phloretin (60 μM) showed marked suppression of invasion and migration through downregulation of matrix metalloproteinase (MMP)-2, MMP-3, and cathepsin S in human SiHa cervical cancer cells. Phloretin (60 μM) reversed the epithelial-mesenchymal transition induced by transforming growth factor-β1 and downregulated mesenchymal markers, such as fibronectin, vimentin, and RhoA. Phloretin (100 μM) treatment significantly inhibited the aldehyde dehydrogenase 1 activity of SiHa cells, reduced the self-renewal properties and stemness signatures of CD44 and Sox-2 in sphere-forming cervical cancer-derived tumor-initiating cells, and inhibited the invasion, MMP-2 activity, and tube formation capacity of human umbilical vein endothelial cells. The ability of phloretin (20 mg/kg) to suppress lung metastasis and tumor growth in SiHa cells was evidenced by tail vein injection and subcutaneous inoculation in a tumor xenograft model. CONCLUSION: In summary, the findings indicate that phloretin inhibits the metastatic and angiogenic abilities and cancer stemness of SiHa cells, thereby suggesting that this flavonoid is a promising therapeutic agent for the treatment of human cervical cancer cells.
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