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
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.
