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.).
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.)
J Pharmacol Exp Ther. 2020 Apr;373(1):149-159. doi: 10.1124/jpet.119.263434. Epub 2020 Feb 3.
Aberrant activation of the Wnt/-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/-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 -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 -catenin, several Wnt target genes, and CSC marker genes. Collectively, the results of our study present that CDDO-Me is a potent Wnt/-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.
Wnt/-catenin 信号通路的异常激活导致多种癌症的发生，包括乳腺癌。因此，开发针对该信号通路的治疗药物是当务之急。在本研究中，我们发现 2-氰基-3,12-二氧代齐墩果-1,9(11)-二烯-28-酸甲酯（CDDO-Me）主要通过靶向低密度脂蛋白受体相关蛋白（LRP）6 和卷曲蛋白（FZD）7 受体复合物抑制 Wnt/-catenin 信号通路。该化合物通过溶酶体途径诱导 LRP6 和 Fzd7 的降解和泛素化。我们进一步表明，CDDO-Me 介导 FZD7 在 LRP6 外显子依赖性方式下降解。在乳腺癌细胞中，CDDO-Me 处理增加了 LRP6 和 FZD7 的降解，并降低了磷酸化 DVL2 和活性-β-catenin 的水平，导致 Wnt 靶基因和几种癌症干细胞（CSC）标记基因下调。在携带鼠乳腺肿瘤病毒（MMTV）-Wnt1 驱动的乳腺肿瘤的小鼠异种移植模型中，CDDO-Me 的给药显著抑制肿瘤生长，并伴有磷酸化和总 LRP6、磷酸化和未磷酸化 DVL2、活性-β-catenin、几个 Wnt 靶基因和 CSC 标记基因表达下调。总之，我们的研究结果表明，CDDO-Me 是一种有效的 Wnt/-catenin 信号抑制剂，可能是一种有前途的治疗乳腺癌的药物。
阻断由低密度脂蛋白受体相关蛋白（LRP）6 和卷曲蛋白（FZD）7 组成的膜受体复合物可能有助于开发包括乳腺癌在内的癌症的治疗方法。我们的研究表明，2-氰基-3,12-二氧代齐墩果-1,9(11)-二烯-28-酸甲酯（CDDO-Me）可以通过溶酶体途径诱导 LRP6/FZD7 膜受体复合物的泛素化和降解来抑制 Wnt/β-catenin 信号通路。我们还发现，LRP6 的外显子对于 CDDO-Me 诱导的 FZD7 降解是必需的。将 CDDO-Me 定义为 Wnt/β-catenin 信号的新型抑制剂，我们的结果为其抗癌活性的机制提供了深入了解。
