Targeting cancer stem cell through blocking the Erk pathway with Kazinol-E from Broussonetia kazinoki

Abstract

Growing evidence suggests that a small population of cells, called cancer stem cells (CSCs) contribute to the heterogeneity, recurrence and resistance to chemotherapy in breast cancer. In this regard, CSC is considered to be a good target to cure breast cancers. The extracellular signal-regulated kinase (ERK) signaling pathway is one of the major determinants in the control of diverse cellular process including the maintenance of CSCs. Kazinol-E is an antioxidant flavan purified from the root bark of Broussonetia kazinoki (Moraceae, paper mulberry). In this study, we found the anti CSC effect of Kazinol-E through targeting ERK pathway. It decreased the population of a breast cancer cell (MCF-7) CSCs which are CD44+/CD24- or aldehyde dehydrogenase positive, at the concentration that does not influence the growth of general MCF-7 cells cultured with serum. It targeted and inhibited ERK kinase activities in vivo in both CSC and in regular cultured cells suggesting the CSCs depend more than the rest of cancer cells do on Erk signaling for the survival. In vitro kinase assay using purified Erk-1 and p90RSK2, as the substrate, and the molecular docking study suggest that the Kazinol-E suppress the Erk activity by direct binding to the ATP binding pocket of Erk-1. Interestingly, a Kazinol-C which is very similar with Kazinol-E in structure did not show the Erk-1 inhibition nor anti CSC activity. These results collectively suggest that Kazinol-E may be a specific anti CSC agent targeting Erk pathway.