Inactivation of AKT, ERK and NF-κB by genistein derivative, 7-difluoromethoxyl-5,4′-di-n-octylygenistein, reduces ovarian carcinoma oncogenicity

Cancer stem cells (CSCs) have central functions in cancer formation and development. Aberrant expression of AKT, ERK and NF-κB signaling pathways have been reported in several types of CSCs. Phytochemicals from dietary compounds possess anti-CSC properties, and have been characterized as promising therapeutic agents for the prevention and treatment of many types of cancers. We previously showed that the newly synthesized genistein derivative, 7-difluoromethoxyl-5,4′-di-n-octylygenistein (DFOG), can inhibit the self-renewal ability of ovarian cancer stem cells (OVCSLCs). In the present study, we further assessed whether various signaling pathways are regulated by DFOG. We found that spheroids derived from the SKOV3 cell line possessed OVCSLC properties and DFOG efficiently inhibited the stemness of the OVCSLCs. In addition, the suppression of spheroid and colony formation by DFOG was associated with inhibition of AKT and ERK1/2 protein phosphorylation, and NF-κB activity in OVCSLCs from the SKOV3 cells. Importantly, DFOG inhibited the oncogenicity of the OVCSLCs by activation of FoxO3a and/or inactivation of FoxM1 by the targeting of multiple pro-survival (AKT and ERK1/2) and proinflammatory (NF-κB) pathways, providing a new avenue for the treatment of ovarian carcinoma in humans.