PMID- 32015160
OWN - NLM
STAT- MEDLINE
DCOM- 20200908
LR  - 20210716
IS  - 1521-0103 (Electronic)
IS  - 0022-3565 (Linking)
VI  - 373
IP  - 1
DP  - 2020 Apr
TI  - CDDO-Me Elicits Anti-Breast Cancer Activity by Targeting LRP6 and FZD7 Receptor 
      Complex.
PG  - 149-159
LID - 10.1124/jpet.119.263434 [doi]
AB  - Aberrant activation of the Wnt/beta-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/beta-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 beta-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 
      beta-catenin, several Wnt target genes, and CSC marker genes. Collectively, the 
      results of our study present that CDDO-Me is a potent Wnt/beta-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/beta-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/beta-catenin signaling, our results provide insight into the mechanism of its 
      anticancer activity.
CI  - Copyright (c) 2020 by The Author(s).
FAU - Zhou, Liang
AU  - Zhou L
AD  - Guangdong Key Laboratory for Genome Stability & Disease Prevention, Carson 
      International Cancer Center, Department of Pharmacology, Shenzhen University 
      Health Science Center, Shenzhen, Guangdong, China (L.Z., Z.W., S.Y., Y.X., J.F., 
      Z.S., J.S., S.L., Q.S., D.L.) and Department of Dermatology, Shenzhen University 
      General Hospital, Shenzhen, Guangdong, China (Y.L.).
FAU - Wang, Zhongyuan
AU  - Wang Z
AD  - Guangdong Key Laboratory for Genome Stability & Disease Prevention, Carson 
      International Cancer Center, Department of Pharmacology, Shenzhen University 
      Health Science Center, Shenzhen, Guangdong, China (L.Z., Z.W., S.Y., Y.X., J.F., 
      Z.S., J.S., S.L., Q.S., D.L.) and Department of Dermatology, Shenzhen University 
      General Hospital, Shenzhen, Guangdong, China (Y.L.).
FAU - Yu, Shubin
AU  - Yu S
AD  - Guangdong Key Laboratory for Genome Stability & Disease Prevention, Carson 
      International Cancer Center, Department of Pharmacology, Shenzhen University 
      Health Science Center, Shenzhen, Guangdong, China (L.Z., Z.W., S.Y., Y.X., J.F., 
      Z.S., J.S., S.L., Q.S., D.L.) and Department of Dermatology, Shenzhen University 
      General Hospital, Shenzhen, Guangdong, China (Y.L.).
FAU - Xiong, Yanpeng
AU  - Xiong Y
AD  - Guangdong Key Laboratory for Genome Stability & Disease Prevention, Carson 
      International Cancer Center, Department of Pharmacology, Shenzhen University 
      Health Science Center, Shenzhen, Guangdong, China (L.Z., Z.W., S.Y., Y.X., J.F., 
      Z.S., J.S., S.L., Q.S., D.L.) and Department of Dermatology, Shenzhen University 
      General Hospital, Shenzhen, Guangdong, China (Y.L.).
FAU - Fan, Jiaoyang
AU  - Fan J
AD  - Guangdong Key Laboratory for Genome Stability & Disease Prevention, Carson 
      International Cancer Center, Department of Pharmacology, Shenzhen University 
      Health Science Center, Shenzhen, Guangdong, China (L.Z., Z.W., S.Y., Y.X., J.F., 
      Z.S., J.S., S.L., Q.S., D.L.) and Department of Dermatology, Shenzhen University 
      General Hospital, Shenzhen, Guangdong, China (Y.L.).
FAU - Lyu, Yansi
AU  - Lyu Y
AD  - Guangdong Key Laboratory for Genome Stability & Disease Prevention, Carson 
      International Cancer Center, Department of Pharmacology, Shenzhen University 
      Health Science Center, Shenzhen, Guangdong, China (L.Z., Z.W., S.Y., Y.X., J.F., 
      Z.S., J.S., S.L., Q.S., D.L.) and Department of Dermatology, Shenzhen University 
      General Hospital, Shenzhen, Guangdong, China (Y.L.).
FAU - Su, Zijie
AU  - Su Z
AD  - Guangdong Key Laboratory for Genome Stability & Disease Prevention, Carson 
      International Cancer Center, Department of Pharmacology, Shenzhen University 
      Health Science Center, Shenzhen, Guangdong, China (L.Z., Z.W., S.Y., Y.X., J.F., 
      Z.S., J.S., S.L., Q.S., D.L.) and Department of Dermatology, Shenzhen University 
      General Hospital, Shenzhen, Guangdong, China (Y.L.).
FAU - Song, Jiaxing
AU  - Song J
AD  - Guangdong Key Laboratory for Genome Stability & Disease Prevention, Carson 
      International Cancer Center, Department of Pharmacology, Shenzhen University 
      Health Science Center, Shenzhen, Guangdong, China (L.Z., Z.W., S.Y., Y.X., J.F., 
      Z.S., J.S., S.L., Q.S., D.L.) and Department of Dermatology, Shenzhen University 
      General Hospital, Shenzhen, Guangdong, China (Y.L.).
FAU - Liu, Shanshan
AU  - Liu S
AD  - Guangdong Key Laboratory for Genome Stability & Disease Prevention, Carson 
      International Cancer Center, Department of Pharmacology, Shenzhen University 
      Health Science Center, Shenzhen, Guangdong, China (L.Z., Z.W., S.Y., Y.X., J.F., 
      Z.S., J.S., S.L., Q.S., D.L.) and Department of Dermatology, Shenzhen University 
      General Hospital, Shenzhen, Guangdong, China (Y.L.).
FAU - Sun, Qi
AU  - Sun Q
AD  - Guangdong Key Laboratory for Genome Stability & Disease Prevention, Carson 
      International Cancer Center, Department of Pharmacology, Shenzhen University 
      Health Science Center, Shenzhen, Guangdong, China (L.Z., Z.W., S.Y., Y.X., J.F., 
      Z.S., J.S., S.L., Q.S., D.L.) and Department of Dermatology, Shenzhen University 
      General Hospital, Shenzhen, Guangdong, China (Y.L.).
FAU - Lu, Desheng
AU  - Lu D
AD  - Guangdong Key Laboratory for Genome Stability & Disease Prevention, Carson 
      International Cancer Center, Department of Pharmacology, Shenzhen University 
      Health Science Center, Shenzhen, Guangdong, China (L.Z., Z.W., S.Y., Y.X., J.F., 
      Z.S., J.S., S.L., Q.S., D.L.) and Department of Dermatology, Shenzhen University 
      General Hospital, Shenzhen, Guangdong, China (Y.L.) delu@szu.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200203
PL  - United States
TA  - J Pharmacol Exp Ther
JT  - The Journal of pharmacology and experimental therapeutics
JID - 0376362
RN  - 0 (Antineoplastic Agents)
RN  - 0 (FZD7 protein, human)
RN  - 0 (Frizzled Receptors)
RN  - 0 (LRP6 protein, human)
RN  - 0 (Low Density Lipoprotein Receptor-Related Protein-6)
RN  - 6SMK8R7TGJ (Oleanolic Acid)
RN  - CEG1Q6OGU1 (bardoxolone methyl)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/*administration & dosage
MH  - Breast Neoplasms/drug therapy/*metabolism
MH  - Dose-Response Relationship, Drug
MH  - Drug Delivery Systems/*methods
MH  - Female
MH  - Frizzled Receptors/*metabolism
MH  - HEK293 Cells
MH  - Humans
MH  - Low Density Lipoprotein Receptor-Related Protein-6/*metabolism
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Transgenic
MH  - Oleanolic Acid/administration & dosage/*analogs & derivatives
MH  - Random Allocation
MH  - Xenograft Model Antitumor Assays/methods
EDAT- 2020/02/06 06:00
MHDA- 2020/09/09 06:00
CRDT- 2020/02/05 06:00
PHST- 2019/10/28 00:00 [received]
PHST- 2020/01/21 00:00 [accepted]
PHST- 2020/02/06 06:00 [pubmed]
PHST- 2020/09/09 06:00 [medline]
PHST- 2020/02/05 06:00 [entrez]
AID - jpet.119.263434 [pii]
AID - 10.1124/jpet.119.263434 [doi]
PST - ppublish
SO  - J Pharmacol Exp Ther. 2020 Apr;373(1):149-159. doi: 10.1124/jpet.119.263434. Epub 
      2020 Feb 3.