Augmentation of differentiation and gap junction function by kaempferol in partially differentiated colon cancer cells.

Kaempferol induces differentiation in partially differentiated colon cancer cells which express low levels of connexin43 protein and connexin43 mRNA (KNC cells). Differentiation was observed as changes in cell morphology and the activity of alkaline phosphatase. Increased differentiation in kaempferol-treated KNC cells correlated with restoration of gap junctional intercellular communication (GJIC), increased levels of connexin43 protein and its phosphorylation status. Phosphorylation (activation) of Stat3 and Erk was also reduced by kaempferol. An inhibitor of Stat3 phosphorylation also induced morphological changes in KNC cells similar to those in kaempferol-treated cells, suggesting that kaempferol-induced differentiation may be mediated by inhibition of Stat3 phosphorylation. These effects were not observed in HCT116 cells, a poorly differentiated colon cancer cell line deficient in expression of connexin43 mRNA and connexin43 protein. In conclusion, kaempferol might function as an anticancer agent by re-establishing GJIC through enhancement of the expression and phosphorylation of connexin43 protein in a tumorigenic colon cancer cell line that already expresses connexin43 mRNA via a Stat3-dependent mechanism. In contrast, kaempferol had no effect in a tumorigenic colon cancer cell line that did not express connexin43 mRNA and was deficient in GJIC.