Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10815309 | Cellular Signalling | 2014 | 7 Pages |
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 5â²-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 IC50 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 IC50 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.
Keywords
eukaryotic initiation factor 4E binding protein 1Protein Kinase C-δp70 S6 kinaseLRP6mTORC1 signalingPKCδfrizzledFZDmTORC14E-BP1eIF4ECK1GSK3βAMPKTNBCFBSp70S6KAPCTCF/LEFadenomatous polyposis coliRottlerinCancerTriple negative breast cancerfetal bovine serumWnt signalingConditioned mediumeukaryotic initiation factor 4E5′-AMP-activated protein Kinasecasein kinase 1Drug discoveryGlycogen synthase kinase-3β
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Authors
Wenyan Lu, Cuihong Lin, Yonghe Li,