The aberrant activation of the Wnt/β-catenin signaling pathway is closely associated with the development of various carcinomas, especially colorectal cancers (CRCs), where adenomatous colorectal polyposis (APC) mutations are the most frequently observed, which limits the anti-tumor efficiency of inhibitors targeting the upstream of Wnt/β-catenin pathway. The anti-tumor activity of the naturally occurring alkaloid cepharanthine (CEP) extracted from the plant Stephania cepharantha Hayata has been reported in various types of tumors. We previously observed that its derivatives inhibited the Wnt/β-catenin signaling in liver cancer; however, the specific mechanism remains unknown. In this study, we confirmed CEP can effectively inhibit APC-mutant CRC cell lines (SW480, SW620, LoVo) through disturbing of the Wnt/β-catenin signaling and elucidated the underlying mechanisms. Here, we demonstrate that CEP attenuates the Wnt/β-catenin signaling by decreasing the β-catenin, subsequently impeding the proliferation of APC-mutant CRCs. Moreover, CEP induced β-catenin transcription inhibition rather than the instability of β-catenin protein and mRNA contributes to reduction of β-catenin. Taken together, our findings identify CEP as the first β-catenin transcriptional inhibitor in the modulation of Wnt/β-catenin signaling and indicate CEP as a potential therapeutic option for the treatment of APC-mutated CRCs.

Graphical Abstract

中文翻译：

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Cepharanthine 通过下调 β-catenin 的表达来抑制 APC 突变型结直肠癌

Wnt/β-catenin信号通路的异常激活与多种癌症的发生密切相关，尤其是结直肠癌（CRC），其中最常见的是腺瘤性结直肠息肉病（APC）突变，这限制了抗肿瘤效率针对 Wnt/β-catenin 通路上游的抑制剂。据报道，从植物Stephania cepharantha Hayata中提取的天然生物碱千金藤碱 (CEP) 在多种类型的肿瘤中具有抗肿瘤活性。我们之前观察到其衍生物抑制肝癌中的Wnt/β-catenin信号传导；然而，具体机制仍不清楚。在这项研究中，我们证实 CEP 可以通过干扰 Wnt/β-catenin 信号传导有效抑制APC突变的 CRC 细胞系（SW480、SW620、LoVo），并阐明其潜在机制。在这里，我们证明 CEP 通过减少 β-catenin 来减弱 Wnt/β-catenin 信号传导，随后阻碍APC突变 CRC 的增殖。此外，CEP 诱导 β-catenin 转录抑制，而不是 β-catenin 蛋白和 mRNA 的不稳定导致 β-catenin 减少。综上所述，我们的研究结果确定 CEP 是调节 Wnt/β-catenin 信号传导的第一个 β-catenin 转录抑制剂，并表明 CEP 是治疗APC突变 CRC 的潜在治疗选择。

图形概要