摘要
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 bcatenin 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.
基金
supported by the National Natural Science Foundation of China(No.81903654 and 81773941)
Program for Professor of Special Appointment(Young Eastern Scholar)at Shanghai Institutions of Higher Learning(QD2018035,China)
Shanghai“Chenguang Program”of Education Commission of Shanghai Municipality(No.18CG46,China)
Shanghai Sailing Program(No.19YF1449400,China)
Ruijin Youth NSFC Cultivation Fund(KY20194297,China)
National Key Subject of Drug Innovation(2019ZX09201005-007,China)
National Key R&D Program for key research project of modernization of traditional Chinese medicine(2019YFC1711602,China)。
