Anticancer properties of Garcinia indica-derived
garcinol are just beginning to be elucidated. We have earlier reported its
cancer cell-specific induction of apoptosis in
breast cancer cells, which was mediated through the downregulation of NF-κB signaling pathway. To gain further mechanistic insight, here, we show for the first time that
garcinol effectively reverses epithelial-to-mesenchymal transition (EMT), that is, it induces mesenchymal-to-epithelial transition (MET) in aggressive triple-negative MDA-MB-231 and BT-549
breast cancer cells. This was associated with upregulation of epithelial marker
E-cadherin and downregulation of mesenchymal markers
vimentin, ZEB-1, and ZEB-2. We also found that
garcinol upregulates the expression of miR-200 and let-7 family
microRNAs (
miRNAs), which provides a molecular mechanism for the observed reversal of EMT to MET. Transfection of cells with NF-κB p65 subunit attenuated the effect of
garcinol on apoptosis induction through reversal of MET to EMT. Forced transfection of p65 and anti-miR-200s could also reverse the inhibitory effect of
garcinol on
breast cancer cell invasion. Moreover, treatment with
garcinol resulted in increased phosphorylation of β-
catenin concomitant with its reduced nuclear localization. The results were also validated in vivo in a xenograft mouse model where
garcinol was found to inhibit NF-κB,
miRNAs,
vimentin, and nuclear β-
catenin. These novel findings suggest that the anticancer activity of
garcinol against aggressive
breast cancer cells is, in part, due to reversal of EMT phenotype, which is mechanistically linked with the deregulation of miR-200s, let-7s, NF-κB, and Wnt signaling pathways.