College of Pharmacy, Natural Products Research Institute, Seoul National University, Seoul 08826, Republic of Korea.
Jaseng Spine and Joint Research Institute, Jaseng Medical Foundation, Seoul 06017, Republic of Korea.
Biochem Pharmacol. 2018 Jun;152:71-83. doi: 10.1016/j.bcp.2018.03.009. Epub 2018 Mar 10.
Colorectal cancer (CRC) is the most common malignant disease worldwide due to its metastasis via the epithelial-mesenchymal transition (EMT) process. E-cadherin and Wnt signaling are emerging as potential targets for suppressing the EMT. In this context, Axin2 has been recognized as a negative regulator that inhibits glycogen synthase kinase 3β (GSK3β)-mediated degradation of Snail1, a transcriptional repressor of E-cadherin. However, Axin2 can also impede Wnt signaling via β-catenin degradation. Therefore, Axin2 may serve as either a promoter or suppressor of tumors, and the effects of its inhibition on the cell proliferation and metastasis of CRC require further elucidation. Here, esculetin (ES), a coumarin, was found to have the most potential effects on both β-catenin-responsive transcriptional and E-cadherin promoter activities. ES also showed anti-proliferative and anti-invasive activities in CRC cells. Mechanistically, Axin2 suppression by ES contributed to E-cadherin-mediated Wnt signaling inhibition. Moreover, the ability of ES to inhibit tumor growth and metastasis via Axin2 suppression was further supported in an HCT116-implanted orthotopic mouse model. Collectively, these findings suggest that targeting the Axin2/E-cadherin axis by ES may be an attractive therapeutic strategy for the treatment of metastatic CRC.
结直肠癌（CRC）是世界上最常见的恶性疾病，因为它通过上皮-间充质转化（EMT）过程转移。E-钙黏蛋白和 Wnt 信号通路正成为抑制 EMT 的潜在靶点。在这种情况下，Axin2 已被认为是一种负调节剂，可抑制糖原合酶激酶 3β（GSK3β）介导的 Snail1 的降解，Snail1 是 E-钙黏蛋白的转录抑制剂。然而，Axin2 也可以通过β-连环蛋白降解来阻碍 Wnt 信号通路。因此，Axin2 可能作为肿瘤的促进剂或抑制剂，其抑制作用对 CRC 细胞的增殖和转移的影响需要进一步阐明。在这里，发现香豆素素（ES）对β-连环蛋白反应性转录和 E-钙黏蛋白启动子活性都有最大的潜在影响。ES 还显示出对 CRC 细胞的增殖和侵袭活性的抑制作用。从机制上讲，ES 通过抑制 Axin2 促进了 E-钙黏蛋白介导的 Wnt 信号抑制。此外，在 HCT116 植入的原位小鼠模型中，通过抑制 Axin2 抑制 ES 抑制肿瘤生长和转移的能力得到了进一步支持。综上所述，这些发现表明，通过 ES 靶向 Axin2/E-钙黏蛋白轴可能是治疗转移性 CRC 的一种有吸引力的治疗策略。
