G protein-coupled receptors(GPCRs)are significant drug targets,but their potential in cancer therapy remains underexplored.Conventional GPCR agonists or antagonists have shown limited effectiveness in cancer treatment...G protein-coupled receptors(GPCRs)are significant drug targets,but their potential in cancer therapy remains underexplored.Conventional GPCR agonists or antagonists have shown limited effectiveness in cancer treatment,necessitating new GPCR-targeting strategies for more effective therapies.This study discovers that Yersinia pestis LcrV,a crucial linker protein for plague infection,acts as a biased agonist of a GPCR,the formyl peptide receptor 1(FPR1).The LcrV protein induces unique conformational changes in FPR1,resulting in G proteins being activated in a distinctive state without subunit dissociation.This leads to a biased signaling profile characterized by cyclic adenosine monophosphate(cAMP)responses andβ-arrestin2 recruitment,but not calcium mobilization.In FPR1-expressing triple-negative breast cancer(TNBC)cells,LcrV bi-directionally modulates intracellular signaling pathways,downregulating extracellular signal-regulated kinases(ERK1/2)and Akt pathways while upregulating Jun N-terminal kinase(JNK)and p38 pathways.This dual modulation results in cell cycle arrest and the inhibition of TNBC cell proliferation.In TNBC xenograft mouse models,long-term LcrV treatment inhibits tumor growth more effectively than a conventional FPR1 antagonist.Additionally,LcrV treatment reprograms tumor cells by reducing stemness-associated proteins OCT4 and c-MYC.Our findings highlight the potential of biased GPCR agonists as a novel GPCR-targeting strategy for cancer treatment.展开更多
Dear Editor,Takeda G protein-coupled receptor 5(TGR5),also known as G protein-coupled bile acids(BAs)receptor 1(GPBAR1),1 belongs to the class A GPCR subfamily.The major TGR5-dependent actions of BAs include maintaini...Dear Editor,Takeda G protein-coupled receptor 5(TGR5),also known as G protein-coupled bile acids(BAs)receptor 1(GPBAR1),1 belongs to the class A GPCR subfamily.The major TGR5-dependent actions of BAs include maintaining energy homeostasis,regulating glucose/lipids metabolism,as well as immunosuppressive properties.2 TGR5 is identified as a potential therapeutic target for protecting hepatocytes from bile acid overload,preventing atherosclerosis,and inhibiting macrophage inflammation due to its critical role in bile acid sensitization.Thus,elucidation of structural characteristics of TGR5 and its activation mechanism would benefit the discovery of therapeutic drugs for these metabolic disorders.展开更多
基金supported by National Natural Science Foundation of China(Nos.82202910 and 81603158)Jiangnan University Medical Discipline Development Funds(Nos.YXXK2024092612 and YXXK2024092602,China)+2 种基金Yunnan Key Research and Development Program Grant(No.202402AA310032,R.D.Y.,China)Shenzhen Medical Research Fund(No.SMRF-D2403009,R.D.Y.,China)the Fundamental Research Funds for the Central Universities(No.JUSRP123072,China).
文摘G protein-coupled receptors(GPCRs)are significant drug targets,but their potential in cancer therapy remains underexplored.Conventional GPCR agonists or antagonists have shown limited effectiveness in cancer treatment,necessitating new GPCR-targeting strategies for more effective therapies.This study discovers that Yersinia pestis LcrV,a crucial linker protein for plague infection,acts as a biased agonist of a GPCR,the formyl peptide receptor 1(FPR1).The LcrV protein induces unique conformational changes in FPR1,resulting in G proteins being activated in a distinctive state without subunit dissociation.This leads to a biased signaling profile characterized by cyclic adenosine monophosphate(cAMP)responses andβ-arrestin2 recruitment,but not calcium mobilization.In FPR1-expressing triple-negative breast cancer(TNBC)cells,LcrV bi-directionally modulates intracellular signaling pathways,downregulating extracellular signal-regulated kinases(ERK1/2)and Akt pathways while upregulating Jun N-terminal kinase(JNK)and p38 pathways.This dual modulation results in cell cycle arrest and the inhibition of TNBC cell proliferation.In TNBC xenograft mouse models,long-term LcrV treatment inhibits tumor growth more effectively than a conventional FPR1 antagonist.Additionally,LcrV treatment reprograms tumor cells by reducing stemness-associated proteins OCT4 and c-MYC.Our findings highlight the potential of biased GPCR agonists as a novel GPCR-targeting strategy for cancer treatment.
基金supported by the National Natural Science Foundation of China(Project No.31971218)Shenzhen Science and Technology Innovation Committee(Projects No.JCYJ20180307151618765 and JCYJ20180508163206306).R.R.was also supported in part by Kobilka Institute of Innovative Drug Discovery and Presidential Fellowship at the Chinese University of Hong Kong,Shenzhen.G.C.was supported in part by Ganghong Young Scholar Fund.
文摘Dear Editor,Takeda G protein-coupled receptor 5(TGR5),also known as G protein-coupled bile acids(BAs)receptor 1(GPBAR1),1 belongs to the class A GPCR subfamily.The major TGR5-dependent actions of BAs include maintaining energy homeostasis,regulating glucose/lipids metabolism,as well as immunosuppressive properties.2 TGR5 is identified as a potential therapeutic target for protecting hepatocytes from bile acid overload,preventing atherosclerosis,and inhibiting macrophage inflammation due to its critical role in bile acid sensitization.Thus,elucidation of structural characteristics of TGR5 and its activation mechanism would benefit the discovery of therapeutic drugs for these metabolic disorders.
