A Bacterial Metabolite, Compound K, Induces Programmed Necrosis in MCF-7 Cells <i>via</i> GSK3β

Abstract

Ginsenosides, the major active component of ginseng, are traditionally used to treat various diseases, including cancer, inflammation, and obesity. Among these, compound K (CK), an intestinal bacterial metabolite of the ginsenosides Rb-1, Rb-2, and Rc from Bacteroides JY-6, is reported to inhibit cancer cell growth by inducing cell-cycle arrest or cell death, including apoptosis and necrosis. However, the precise effect of CK on breast cancer cells remains unclear. MCF-7 cells were treated with CK (0-70 mu M) for 24 or 48 h. Cell proliferation and death were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and flow cytometry assays, respectively. Changes in downstream signaling molecules involved in cell death, including glycogen synthase kinase 3 beta (GSK3 beta), GSK3 beta, beta-catenin, and cyclin D1, were analyzed by western blot assay. To block GSK3 beta signaling, MCF-7 cells were pretreated with GSK3 beta inhibitors 1. h prior to CK treatment. Cell death and the expression of beta-catenin and cyclin D1 were then examined. CK dose- and time-dependently inhibited MCF-7 cell proliferation. Interestingly, CK induced programmed necrosis, but not apoptosis, via the GSK3 beta signaling pathway in MCF-7 cells. CK inhibited GSK3 beta phosphorylation, thereby suppressing the expression of beta-catenin and cyclin D1. Our results suggest that CK induces programmed necrosis in MCF-7 breast cancer cells via the GSK3 beta signaling pathway.