title: Salinomycin suppresses LRP6 expression and inhibits both Wnt/β-catenin and mTORC1 signaling in breast and prostate cancer cells.
abstract: Emerging evidence indicates that activation of Wnt/β-catenin signaling at the cell surface results in inhibition of glycogen synthase kinase 3β (GSK3β), 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/β-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/β-catenin signaling inhibitor, but also a strong mTORC1 signaling antagonist in breast and prostate cancer cells. Mechanistically, salinomycin activated GSK3β in cancer cells. Moreover, salinomycin was able to suppress the expression of cyclin D1 and survivin, two targets of both Wnt/β-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.
authors.affiliation: Drug Discovery Division, Southern Research Institute, 2000 Ninth Avenue South, Birmingham, AL 35255.
authors.forename: Wenyan
authors.initials: W
authors.lastname: Lu
authors.forename: Yonghe
authors.initials: Y
authors.lastname: Li
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001940:Breast / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D019938:Cyclin D1 / Q000096:biosynthesis; D004789:Enzyme Activation; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D057809:HEK293 Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000096:biosynthesis*; D061986:MCF-7 Cells; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D011714:Pyrans / Q000494:pharmacology*; D000077022:Survivin; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000378:metabolism; D000095662:Polyether Polyketides
chemical_list: D000900:Anti-Bacterial Agents; D019938:Cyclin D1; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D051034:Inhibitor of Apoptosis Proteins; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D011714:Pyrans; D000077022:Survivin; D058570:TOR Serine-Threonine Kinases; D051153:Wnt Proteins; D051176:beta Catenin; C107489:BIRC5 protein, human; C555475:LRP6 protein, human; C010327:salinomycin; D000095662:Polyether Polyketides; C000605506:GSK3B protein, human
keywords: CANCER; LRP6; SALINOMYCIN; Wnt SIGNALING; mTORC1 SIGNALING