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 ...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.展开更多
Background:Non-small cell lung cancer(NSCLC)is considered one of the leading causes of cancer-related death.Despite the availability of drugs for the treatment of NSCLC,the need for the development of novel agents wit...Background:Non-small cell lung cancer(NSCLC)is considered one of the leading causes of cancer-related death.Despite the availability of drugs for the treatment of NSCLC,the need for the development of novel agents with high efficiency and fewer adverse effects remains unmet.The natural compound bruceine D(BD)is widely recognized for its notable anti-inflammatory,antiparasitic,and hypoglycemic activities.However,it is unclear whether BD can be used as a novel agent for NSCLC treatment.Materials and Methods:MTT and colony formation assays were used to assess the antiproliferative effect of BD on NSCLC cells.Wound healing and transwell assays were performed to determine the effect of BD on the migration and invasion of H1299 cells,respectively.Western blotting assay was used to detect the expression levels of proteins.Results:We demonstrated that BD significantly inhibited the proliferation of H1299,A549,and H226 cells with respective IC50 values of 6.06±0.52,7.15±0.90,and 7.21±0.75μM.In addition,BD suppressed colony formation of H1299 cells in a dose-dependent manner.Following treatment with BD,the migration and invasive capabilities of H1299 cells were significantly inhibited in a dose-and time-dependent manner.Moreover,the results of Western blotting demonstrated that BD treatment resulted in the upregulation of the protein expression of E-cadherin and downregulation of the expression of N-cadherin,twist,snail,integrinαv,integrinβ4,matrix metalloproteinase-7,andβ-catenin proteins.Conclusion:BD inhibits proliferation,migration,and invasion of NSCLC cells;therefore,BD may be considered for its potential in adjuvant therapy for NSCLC.展开更多
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)+4 种基金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)。
文摘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(81773888,U1903126,and 81902152)Natural Science Foundation of Guangdong Province(2020A1515010605)Open Founding of Key Laboratory Ethnomedicine Ministry of Education(KLEM-KF2019Y03)
文摘Background:Non-small cell lung cancer(NSCLC)is considered one of the leading causes of cancer-related death.Despite the availability of drugs for the treatment of NSCLC,the need for the development of novel agents with high efficiency and fewer adverse effects remains unmet.The natural compound bruceine D(BD)is widely recognized for its notable anti-inflammatory,antiparasitic,and hypoglycemic activities.However,it is unclear whether BD can be used as a novel agent for NSCLC treatment.Materials and Methods:MTT and colony formation assays were used to assess the antiproliferative effect of BD on NSCLC cells.Wound healing and transwell assays were performed to determine the effect of BD on the migration and invasion of H1299 cells,respectively.Western blotting assay was used to detect the expression levels of proteins.Results:We demonstrated that BD significantly inhibited the proliferation of H1299,A549,and H226 cells with respective IC50 values of 6.06±0.52,7.15±0.90,and 7.21±0.75μM.In addition,BD suppressed colony formation of H1299 cells in a dose-dependent manner.Following treatment with BD,the migration and invasive capabilities of H1299 cells were significantly inhibited in a dose-and time-dependent manner.Moreover,the results of Western blotting demonstrated that BD treatment resulted in the upregulation of the protein expression of E-cadherin and downregulation of the expression of N-cadherin,twist,snail,integrinαv,integrinβ4,matrix metalloproteinase-7,andβ-catenin proteins.Conclusion:BD inhibits proliferation,migration,and invasion of NSCLC cells;therefore,BD may be considered for its potential in adjuvant therapy for NSCLC.
