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2014 ; 26
(6
): 1303-9
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gab.com Text
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Rottlerin induces Wnt co-receptor LRP6 degradation and suppresses both
Wnt/?-catenin and mTORC1 signaling in prostate and breast cancer cells
#MMPMID24607787
Lu W
; Lin C
; Li Y
Cell Signal
2014[Jun]; 26
(6
): 1303-9
PMID24607787
show ga
Activation of Wnt/?-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/?-catenin signaling. We found that
rottlerin, a natural plant polyphenol, suppressed LRP6 expression and
phosphorylation, and inhibited Wnt/?-catenin signaling in HEK293 cells.
Furthermore, the inhibitory effects of rottlerin on LRP6
expression/phosphorylation and Wnt/?-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/?-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
?M 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/?-catenin and mTORC1 signaling in prostate and breast cancer
cells. Our data indicate that rottlerin is a novel LRP6 inhibitor and suppresses
both Wnt/?-catenin and mTORC1 signaling in prostate and breast cancer cells, and
that LRP6 represents a potential therapeutic target for cancers.
|*Wnt Signaling Pathway
[MESH]
|Acetophenones/*pharmacology
[MESH]
|Antineoplastic Agents/*pharmacology
[MESH]
|Benzopyrans/*pharmacology
[MESH]
|Breast Neoplasms
[MESH]
|Cell Line, Tumor
[MESH]
|Cell Proliferation/drug effects
[MESH]
|Cyclin D1/metabolism
[MESH]
|Drug Screening Assays, Antitumor
[MESH]
|Female
[MESH]
|HEK293 Cells
[MESH]
|Humans
[MESH]
|Inhibitor of Apoptosis Proteins/metabolism
[MESH]
|Inhibitory Concentration 50
[MESH]
|Low Density Lipoprotein Receptor-Related Protein-6/genetics/*metabolism
[MESH]