肝细胞癌(HCC)是癌症相关死亡的主要原因之一,以高度缺氧的肿瘤微环境为特征。缺氧诱导因子-1α(HIF-1α)是参与细胞对氧水平变化反应的主要调节因子,支持肿瘤细胞适应缺氧。BruceineD(BD)是一种分离的天然类木素,具有多种抗癌作用。这里,我们发现BD可以显著抑制HIF-1α的表达及其随后介导的HCC细胞代谢。使用生物物理蛋白质组学方法,我们确定β-catenin和T细胞因子(ICAT)的抑制剂为BD的功能靶标。通过瞄准ICAT,BD破坏了β-连环蛋白和ICAT的相互作用,并促进β-连环蛋白降解,进而诱导HIF-1α表达的降低。此外,BD可以在体内抑制肝癌细胞增殖和肿瘤生长,和敲除ICAT显著增加了体外对BD治疗的抗性。我们的数据强调了BD作为β-连环蛋白/HIF-1α轴介导的HCC代谢调节剂的潜力。
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths, characterized by highly hypoxic tumor microenvironment. Hypoxia-inducible factor-1α (HIF-1α) is a major regulator involved in cellular response to changes of oxygen levels, supporting the adaptation of tumor cells to hypoxia. Bruceine D (BD) is an isolated natural quassinoid with multiple anti-cancer effects. Here, we identified BD could significantly inhibit the HIF-1α expression and its subsequently mediated HCC cell metabolism. Using biophysical proteomics approaches, we identified inhibitor of β-catenin and T-cell factor (ICAT) as the functional target of BD. By targeting ICAT, BD disrupted the interaction of β-catenin and ICAT, and promoted β-catenin degradation, which in turn induced the decrease of HIF-1α expression. Furthermore, BD could inhibit HCC cells proliferation and tumor growth in vivo, and knockdown of ICAT substantially increased resistance to BD treatment in vitro. Our data highlight the potential of BD as a modulator of β-catenin/HIF-1α axis mediated HCC metabolism.