Li X, Bai B, Liu L, Ma P, Kong L, Yan J, Zhang J, Ye Z, Zhou H, Mao B, Zhu H, Li Y
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences , Kunming 650201, People's Republic of China.
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, People's Republic of China; School of Food and Biological Engineering, Zhengzhou University of Light Industry, Zhengzhou 450002, People's Republic of China.
Cell Death Discov. 2015 Oct 5;1:15033. doi: 10.1038/cddiscovery.2015.33. eCollection 2015.
Wnt signaling pathway is aberrantly activated in a variety of cancers, especially in colorectal cancer (CRC), because of mutations in the genes encoding adenomatous polyposis coli (APC), β-catenin and Axin. Small-molecule antagonists of Wnt/β-catenin signaling are attractive candidates for developing effective therapeutics for CRC. In this study, we have identified a novel Wnt signaling inhibitor, isopropyl 9-ethyl-1- (naphthalen-1-yl)-9H-pyrido[3,4-b]indole-3- carboxylate (Z86). Z86 inhibited Wnt reporter activities and the expression of endogenous Wnt signaling target genes in mammalian cells and antagonized the second axis formation of Xenopus embryos induced by Wnt8. We showed that Z86 treatment inhibits GSK3β (Ser9) phosphorylation, leading to its overactivation and promoting the phosphorylation and degradation of β-catenin. In vitro, Z86 selectively inhibited the growth of CRC cells with constitutive Wnt signaling and caused obvious G1-phase arrest of the cell cycle. Notably, in a nude mouse model, Z86 inhibited dramatically the xenografted tumor growth of CRC. Daily intraperitoneal injection of Z86 at 5 mg/kg resulted in >70% reduction in the tumor weight of HCT116 cell origin that was associated with decreased GSK3β (Ser9) phosphorylation and increased β-catenin phosphorylation. Taken together, our findings provide a novel promising chemotype for CRC therapeutics development targeting the canonical Wnt signaling.
由于编码腺瘤性结肠息肉病（APC）、β-连环蛋白和Axin的基因突变，Wnt信号通路在多种癌症中异常激活，尤其是在结直肠癌（CRC）中。Wnt/β-连环蛋白信号通路的小分子拮抗剂是开发CRC有效治疗药物的有吸引力的候选物。在本研究中，我们鉴定了一种新型Wnt信号抑制剂，9-乙基-1-（萘-1-基）-9H-吡啶并[3,4-b]吲哚-3-羧酸异丙酯（Z86）。Z86抑制哺乳动物细胞中的Wnt报告基因活性和内源性Wnt信号靶基因的表达，并拮抗由Wnt8诱导的非洲爪蟾胚胎的第二轴形成。我们发现Z86处理可抑制GSK3β（Ser9）磷酸化，导致其过度激活，并促进β-连环蛋白的磷酸化和降解。在体外，Z86选择性抑制具有组成性Wnt信号的CRC细胞的生长，并导致细胞周期明显的G1期停滞。值得注意的是，在裸鼠模型中，Z86显著抑制CRC的异种移植肿瘤生长。每天腹腔注射5mg/kg的Z86可使源自HCT116细胞的肿瘤重量减少>70%，这与GSK3β（Ser9）磷酸化降低和β-连环蛋白磷酸化增加有关。综上所述，我们的研究结果为靶向经典Wnt信号的CRC治疗药物开发提供了一种新的有前景的化学类型。
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