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 149
OP 159
DO 10.1124/jpet.119.263434
VO 373
IS 1
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/373/1/149.abstract
AB Aberrant activation of the Wnt/β-catenin pathway leads to the development of multiple cancers, including breast cancer. Development of therapeutic agents against this signaling pathway is an urgent need. In this study, we found that 2-cyano-3, 12-dioxooleana-1, 9(11)-dien-28-oic acid–methyl ester (CDDO-Me) could inhibit Wnt/β-catenin signaling mainly through targeting the low-density lipoprotein receptor–related protein (LRP) 6 and Frizzled (FZD) 7 receptor complex. This compound induced the degradation and ubiquitination of LRP6 and Fzd7 via the lysosomal pathway. We further showed that CDDO-Me mediated the degradation of FZD7 in an LRP6 ectodomain-dependent manner. In breast cancer cells, treatment with CDDO-Me increased the degradation of LRP6 and FZD7 and reduced the levels of phosphorylated Disheveled (DVL) 2 and active β-catenin, resulting in the downregulation of Wnt target genes and several cancer stem cell (CSC) marker genes. In a murine xenograft bearing mouse mammary tumor virus (MMTV)-Wnt1–driven mammary tumor, administration of CDDO-Me significantly inhibited tumor growth and was 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, the results of our study present that CDDO-Me is a potent Wnt/β-catenin signaling inhibitor that may be a promising therapeutic agent against breast cancer.SIGNIFICANCE STATEMENT Blocking the membrane receptor complex consisting of low-density lipoprotein receptor–related protein (LRP) 6 and Frizzled (FZD) 7 may help developing therapeutic approaches for cancers, including breast cancers. Our study indicates that 2-cyano-3, 12-dioxooleana-1, 9(11)-dien-28-oic acid–methyl ester (CDDO-Me) can inhibit Wnt/β-catenin signaling by inducing the ubiquitination and degradation of LRP6/FZD7 membrane receptor complex via a lysosomal pathway. We also found that the ectodomain of LRP6 is essential for CDDO-Me–induced FZD7 degradation. Defining CDDO-Me as a novel inhibitor of Wnt/β-catenin signaling, our results provide insight into the mechanism of its anticancer activity.