Salinomycin Suppresses LRP6 Expression and Inhibits Both Wnt/[beta]-catenin and mTORC1 Signaling in Breast and Prostate Cancer Cells

Emerging evidence indicates that activation of Wnt/[beta]-catenin signaling at the cell surface results in inhibition of glycogen synthase kinase 3[beta] (GSK3[beta]), leading to activation of mTORC1 signaling in cancer cells. The low density lipoprotein receptor-related protein-6 (LRP6) is an essential Wnt co-receptor for Wnt/[beta]-catenin signaling. Salinomycin is a novel small molecule inhibitor of LRP6. In the present study, we found that LRP6 overexpression induced mTORC1 signaling activation in cancer cells, and that salinomycin was not only a potent Wnt/[beta]-catenin signaling inhibitor, but also a strong mTORC1 signaling antagonist in breast and prostate cancer cells. Mechanistically, salinomycin activated GSK3[beta] in cancer cells. Moreover, salinomycin was able to suppress the expression of cyclin D1 and survivin, two targets of both Wnt/[beta]-catenin and mTORC1 signaling, in prostate and breast cancer cells, and displayed remarkable anticancer activity. Our results present novel mechanisms underlying salinomycin-mediated cancer cell death. J. Cell. Biochem. 115: 1799-1807, 2014. © 2014 Wiley Periodicals, Inc.