title: Rottlerin induces Wnt co-receptor LRP6 degradation and suppresses both Wnt/β-catenin and mTORC1 signaling in prostate and breast cancer cells.
abstract: Activation of Wnt/β-catenin signaling can result in up-regulation 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. We found that rottlerin, a natural plant polyphenol, suppressed LRP6 expression and phosphorylation, and inhibited Wnt/β-catenin signaling in HEK293 cells. Furthermore, the inhibitory effects of rottlerin on LRP6 expression/phosphorylation and Wnt/β-catenin signaling were confirmed in human prostate cancer PC-3 and DU145 cells and breast cancer MDA-MB-231 and T-47D cells. Mechanistically, rottlerin promoted LRP6 degradation, but had no effects on LRP6 transcriptional activity. In addition, rottlerin-mediated LRP6 down-regulation was unrelated to activation of 5'-AMP-activated protein kinase (AMPK). Importantly, we also found that rottlerin inhibited mTORC1 signaling in prostate and breast cancer cells. Finally, we demonstrated that rottlerin 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 with IC(50) values between 0.7 and 1.7 μM for prostate cancer PC-3 and DU145 cells and breast cancer MDA-MB-231 and T-47D cells. The IC(50) values are comparable to those shown to suppress the activities of Wnt/β-catenin and mTORC1 signaling in prostate and breast cancer cells. Our data indicate that rottlerin is a novel LRP6 inhibitor and suppresses both Wnt/β-catenin and mTORC1 signaling in prostate and breast cancer cells, and that LRP6 represents a potential therapeutic target for cancers.
authors.affiliation: Department of Biochemistry and Molecular Biology, Drug Discovery Division, Southern Research Institute, 2000 Ninth Avenue South, Birmingham, AL 35255, USA.
authors.forename: Wenyan
authors.initials: W
authors.lastname: Lu
authors.affiliation: Department of Biochemistry and Molecular Biology, Drug Discovery Division, Southern Research Institute, 2000 Ninth Avenue South, Birmingham, AL 35255, USA; Department of Pharmacy, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.
authors.forename: Cuihong
authors.initials: C
authors.lastname: Lin
authors.affiliation: Department of Biochemistry and Molecular Biology, Drug Discovery Division, Southern Research Institute, 2000 Ninth Avenue South, Birmingham, AL 35255, USA. Electronic address: y.li@souternresearch.org.
authors.forename: Yonghe
authors.initials: Y
authors.lastname: Li
mesh_terms: D000098:Acetophenones / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology*; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D020128:Inhibitory Concentration 50; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms; D059748:Proteolysis; D000077022:Survivin; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D060449:Wnt Signaling Pathway; D060509:Wnt3A Protein / Q000378:metabolism
chemical_list: D000098:Acetophenones; D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D001578:Benzopyrans; C530104:CCND1 protein, human; D051034:Inhibitor of Apoptosis Proteins; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D046912:Multiprotein Complexes; D000077022:Survivin; C555510:WNT3A protein, human; D060509:Wnt3A Protein; D019938:Cyclin D1; C085746:rottlerin; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
keywords: Cancer; Drug discovery; LRP6; Rottlerin; Wnt signaling; mTORC1 signaling