Curcumin and Emodin Down-Regulate TGF-β Signaling Pathway in Human Cervical Cancer Cells

Cervical cancer is the major cause of cancer related deaths in women, especially in developing countries and Human Papilloma Virus infection in conjunction with multiple deregulated signaling pathways leads to cervical carcinogenesis. TGF-beta signaling in later stages of cancer is known to induce epithelial to mesenchymal transition promoting tumor growth. Phytochemicals, curcumin and emodin, are effective as chemopreventive and chemotherapeutic compounds against several cancers including cervical cancer. The main objective of this work was to study the effect of curcumin and emodin on TGF-beta signaling pathway and its functional relevance to growth, migration and invasion in two cervical cancer cell lines, SiHa and HeLa. Since TGF-beta and Wnt/beta-catenin signaling pathways are known to cross talk having common downstream targets, we analyzed the effect of TGF-beta on beta-catenin (an important player in Wnt/beta-catenin signaling) and also studied whether curcumin and emodin modulate them. We observed that curcumin and emodin effectively down regulate TGF-beta signaling pathway by decreasing the expression of TGF-beta Receptor II, P-Smad3 and Smad4, and also counterbalance the tumorigenic effects of TGF-beta by inhibiting the TGF-beta-induced migration and invasion. Expression of downstream effectors of TGF-beta signaling pathway, cyclinD1, p21 and Pin1, was inhibited along with the down regulation of key mesenchymal markers (Snail and Slug) upon curcumin and emodin treatment. Curcumin and emodin were also found to synergistically inhibit cell population and migration in SiHa and HeLa cells. Moreover, we found that TGF-beta activates Wnt/beta-catenin signaling pathway in HeLa cells, and curcumin and emodin down regulate the pathway by inhibiting beta-catenin. Taken together our data provide a mechanistic basis for the use of curcumin and emodin in the treatment of cervical cancer.