Abstract
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.
Footnotes
- Received October 28, 2019.
- Accepted January 21, 2020.
↵1 L.Z. and Z.W. contributed equally to this work.
This work was supported by the National Nature Science Foundation of China (Grants 31870754, 31970739, and 31501143), the Nature Science Foundation of Guangdong Province (Grant 2014A030310168), the Shenzhen Peacock Innovation Team Project (Grant KQTD20140630100658078), the Shenzhen Peacock Plan (Grants 827000183 and 827000186), the Shenzhen Basic Research Program (Grants JCYJ20150525092941006, JCYJ20170302143447936, and JCYJ20170817094611664), and SZU Medical Young Scientists Program (71201-000001).
↵This article has supplemental material available at jpet.aspetjournals.org.
- Copyright © 2020 by The Author(s)
This is an open access article distributed under the CC BY-NC Attribution 4.0 International license.