Bruceine D inhibits HIF-1α-mediated glucose metabolism in hepatocellular carcinoma by blocking ICAT/β-catenin interaction

• 作者: Rui Huang Lijun Zhang Jinmei Jin Yudong Zhou Hongwei Zhang Chao Lv Dong Lu Ye Wu Hong Zhang Sanhong Liu Hongzhuan Chen Xin Luan Weidong Zhang
• 来源期刊: 药学学报（英文版）
• 年，卷（期）: 2021,（11）
• 所属期刊栏目: Origimal articles
• 页码范围: 3481-3492
• 页数: 12页
• 语种: 英文

摘要

Hepatocellular carcinoma(HCC)is one of the leading causes of cancer-related deaths,char-acterized 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-1αexpression.Furthermore,BD could inhibit HCC cells proliferation and tumor growth in vivo,and knock-down of ICAT substantially increased resistance to BD treatment in vitro.Our data highlight the potential of BD as a modulator of β-catenin/HIF-1 α axis mediated HCC metabolism.