Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China.
Cell Death Dis. 2018 May 22;9(6):591. doi: 10.1038/s41419-018-0645-3.
Aberrant activation of Wnt/β-catenin signalling is critical in the progression of human cancers, especially colorectal cancer (CRC). Therefore, inhibition of Wnt/β-catenin signalling is a significant potential target for CRC therapy. Here, we identified for the first time that Physalin F (PF), a steroid derivative isolated from Physalis angulate, acts as an antagonist of Wnt/β-catenin signalling. In vitro, PF decreased Wnt3a-induced TOPFlash reporter activity in HEK293T cells and promoted the formation of the β-catenin destruction complex. Importantly, PF also inhibited Wnt/β-catenin signalling and accelerated the degradation of β-catenin in CRC cells. However, PF did not affect the stabilization of Axin or the interaction of β-catenin with E-cadherin. Interestingly, we further found that PF promoted YAP binding to the β-catenin destruction complex, which facilitated the ubiquitination and degradation of β-catenin. Silencing and pharmacological inhibition of YAP reversed the formation of the β-catenin destruction complex induced by PF, implying that YAP binding to the β-catenin destruction complex was responsible for PF-mediated inhibition of Wnt/β-catenin signalling. Furthermore, PF observably inhibited tumour growth by down-regulating β-catenin in tumour-bearing mice. Collectively, our findings indicated that PF inhibited Wnt/β-catenin signalling by accelerating the ubiquitination and degradation of β-catenin in a YAP-dependent manner and therefore PF could be a novel potential candidate for CRC therapy.
Wnt/β-catenin 信号通路的异常激活在人类癌症的进展中至关重要，尤其是结直肠癌（CRC）。因此，抑制 Wnt/β-catenin 信号通路是 CRC 治疗的一个重要潜在靶点。在这里，我们首次发现，来源于灯笼草的甾体衍生物 Physalin F（PF）作为 Wnt/β-catenin 信号通路的拮抗剂。在体外，PF 降低了 HEK293T 细胞中 Wnt3a 诱导的 TOPFlash 报告基因活性，并促进了 β-catenin 破坏复合物的形成。重要的是，PF 还抑制了 CRC 细胞中的 Wnt/β-catenin 信号通路，并加速了 β-catenin 的降解。然而，PF 并不影响 Axin 的稳定或 β-catenin 与 E-cadherin 的相互作用。有趣的是，我们进一步发现，PF 促进了 YAP 与 β-catenin 破坏复合物的结合，从而促进了 β-catenin 的泛素化和降解。沉默和药理学抑制 YAP 逆转了 PF 诱导的 β-catenin 破坏复合物的形成，这表明 YAP 与 β-catenin 破坏复合物的结合是 PF 介导的抑制 Wnt/β-catenin 信号通路的原因。此外，PF 通过下调荷瘤小鼠中的 β-catenin 显著抑制了肿瘤生长。总之，我们的研究结果表明，PF 通过 YAP 依赖性方式加速了 β-catenin 的泛素化和降解来抑制 Wnt/β-catenin 信号通路，因此 PF 可能成为 CRC 治疗的一种新型潜在候选药物。
