Several lines of evidence indicate that Fibronectin Extra Domain A (EDA) promotes metastatic capacity of tumor cells by engaging cell surface α9β1 integrins. This interaction mediated by the C-C loop of EDA activates pro-oncogenic signaling pathways leading to epithelial to mesenchymal transition (EMT) of tumor cells, thus signifying its importance in control of metastatic progression. Irigenin showed potent binding-affinity with C-C loop of EDA. It specifically targeted α9β1 and α4β1 integrin binding sites on EDA. Irigenin showed relatively pronounced effect on growth inhibition of A549 and NCI-H522 cells (both are human lung cancer cell lines found to constitutively express Fibronectin isoform containing EDA) with IC50 value of 58 μM and 61 μM in A549 and NCI-H522 respectively. The proliferative abilities of these cells decreased in the presence of Irigenin in a dose-dependent manner. In order to evaluate the effect of Irigenin on the EDA induced metastatic behavior, EDA characterized A549 and NCI-H522 cells were treated with sub-toxic concentrations (10, 25, and 50 μM) of Irigenin for 24 h. Irigenin significantly overcame the migratory abilities of these cells in comparison to control (DMSO) as was reflected by attenuated wound healing. Irigenin treatment showed the inhibition of wound closure in a concentration dependent manner. Moreover, Irigenin significantly inhibited the invasiveness of A549 and NCI-H522 cells as compared to control. The invasive capacity of Irigenin treated-cells was inhibited by 80% and 35% in case of A549 cells and 80% and 40% in NCI-H522 cells at highest and lowest non-cytotoxic concentrations of Irigenin respectively, compared to the control[3].
作用机制
Irigenin specifically targets α9β1 and α4β1 integrin binding sites on EDA comprising LEU46, PHE47, PRO48, GLU58, LEU59 and GLN60 in its C-C loop as evaluated by energy decomposition per residue of Irigenin–EDA complex[3].
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