Downregulation of Wnt/β-catenin self-renewal pathway in cervical cancer cells by polyphenolic compounds

Abstract

Cervical cancer is the second most common cancer in woman of developing countries. Wnt/β-catenin self-renewal pathway is important for cervical cancer initiation and progression. Plumbagin, Pongapin and Karanjin are three plant polyphenols with known anti-cancer activities. Thus, this study aims to analyze the effects of these compounds on Wnt/β-catenin pathway in cervical cancer cells (HeLa), due to their high sensitivity in this cell line. The compounds significantly downregulated the co-receptor LRP6 (low density lipoprotein receptor related protein 6) expression (mRNA/ protein) in HeLa cells without any change in the expression of receptor FZD7 (Frizzled class receptor 7). The low membrane expression of LRP6 seen in the immunocytochemical analysis might be due to upregulation of its antagonist Dickkopf 1 (DKK1) protein. The compounds could also increase the expression of FZD7 antagonists, SFRP1/2 (mRNA/protein) in HeLa cells. The upregulation of SFRPs (secreted frizzled-related protein) was due to their promoter hypomethylation through downregulation of DNMT1 (DNA methyltransferase 1) protein by the compounds. As a result, there was downregulation of effector protein β-catenin and activated phospho-β-catenin (Y654) of the pathway in HeLa cells by these compounds. Thus, the polyphenols differentially inhibit the Wnt/β-catenin pathway to restrict cervical cancer proliferation, suggesting their therapeutic importance.