RT Journal Article
SR Electronic
T1 CDDO-Me elicits anti-breast cancer activity by targeting LRP6 and FZD7 receptor complex
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.119.263434
DO 10.1124/jpet.119.263434
A1 Liang Zhou
A1 Zhongyuan Wang
A1 Shubin Yu
A1 Yanpeng Xiong
A1 Jiaoyang Fan
A1 Yansi Lyu
A1 Zijie Su
A1 Jiaxing Song
A1 Shanshan Liu
A1 Qi Sun
A1 Desheng Lu
YR 2020
UL http://jpet.aspetjournals.org/content/early/2020/02/03/jpet.119.263434.abstract
AB Aberrant activation of the Wnt/β-catenin pathway leads to the development of multiple cancers including breast cancer. There is an urgent need to develop therapeutic agents against this signaling pathway. In this study, we found that CDDO-Me could inhibit Wnt/β-catenin signaling mainly through targeting the LRP6 and FZD7 receptor complex. This compound induced the degradation and ubiquitination of LRP6 and Fzd7 via the lysosomal pathway. We further showed CDDO-Me mediated degradation of FZD7 in a LRP6 ectodomain-dependent manner. In breast cancer cells, treatment with CDDO-Me increased the degradation of LRP6 and Fzd7, reduced the levels of phosphorylated DVL2 and active β-catenin, resulting in downregulation of Wnt target genes and some cancer stem cell (CSC) marker genes. In a murine xenograft bearing MMTV-Wnt1-driven mammary tumor, administration of CDDO-Me significantly inhibited tumor growth, accompanied by reduced expression of phosphorylated and total LRP6, phosphorylated and unphosphorylated DVL2, active β-catenin, several Wnt target genes and CSC marker genes. Collectively, our results demonstrated that CDDO-Me is a potent Wnt/β-catenin signaling inhibitor and so may be a promising therapeutic agent against breast cancer.SIGNIFICANCE STATEMENT Current evidences showed that LRP6 and FZD7 membrane receptor complex play key effect on Wnt/β-catenin activation driven cancers. And block LRP6 or FZD7 by small molecular or antibody may help developing therapeutic approach for cancers including breast cancers. In this study we showed that the small molecular CDDO-ME can inhibits Wnt/β-catenin signaling pathway by inducing LRP6/FZD7 membrane receptor complex ubiquitination and degradation via a lysosomal pathway. And we also found that the ectodomain of LRP6 is very essential for CDDO-ME induced FZD7 degradation. Our results define a novel mechanism for anticancer action of CDDO-Me, and provide evidence for further clinical cancer research.