The Ginsenoside Rg3 Inhibits Manifestation of Breast Cancer Stem Cell-like Properties through Regulation of Self-renewal Signaling

Abstract

Red ginseng extract (RGE) has been reported to exert numerous anti-cancer and other therapeutic effects. Breast cancer cells that express stem-cell associated markers acquire enhanced invasiveness and resistance to chemo-/radiotherapy. In this study, I investigated whether RGE and its pharmacologically active ingredient Rg3 could modulate manifestation of breast cancer stem cell-like properties through regulation of self-renewal signaling. The sphere-forming assay is widely used for identifying stem cells based on their self-renewal capacity. RGE significantly reduced the number and the size of spheroids (mammospheres) in human breast cancer (MCF-7 and MDA-MB-231) cells. Tumorigenic breast cancer stem cells (CSCs) are characterized by enhanced proportion of CD44+/CD24- cells. RGE successfully reduced the CD44+/CD24- populations in a concentration-dependent manner. Furthermore, Rg3, one of the major components of RGE, also reduced the number and the size of mammospheres and the proportion of CD44+/CD24- breast cancer cells. To investigate the mechanism whereby Rg3 regulates the breast cancer stem-like properties, I determined the expression of Sox-2 and Bmi-1 which are involved in self-renewal and stem cell maintenance. Rg3 treatment significantly decreased the expression of these proteins in MCF-7 and MDA-MB-231 mammospheres. Notably, the inhibition of Akt, a kinase that plays a major role in maintaining stem-like properties, resulted in down-regulation of Sox-2 and Bmi-1. In conclusion, RGE and its active ingredient Rg3 inhibit the manifestation of breast cancer stem cell-like properties through suppression of Akt-mediated self-renewal signaling.