Discovery of Yersinia LcrV as a novel biased agonist of formyl peptide receptor 1 to bi-directionally modulate intracellular kinases in triple-negative breast cancer

Discovery of Yersinia LcrV as a novel biased agonist of formyl peptide receptor 1 to bi-directionally modulate intracellular kinases in triple-negative breast cancer

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. Thi...

Full description

Saved in:
Bibliographic Details
Main Authors: Yunjun Ge, Huiwen Guan, Ting Li, Jie Wang, Liang Ying, Shuhui Guo, Jinjian Lu, Richard D. Ye, Guosheng Wu
Format: Article
Language:English
Published: Elsevier 2025-07-01
Series:Acta Pharmaceutica Sinica B
Subjects:
G protein-coupled receptor
Yersinia LcrV
Biased agonist
Formyl peptide receptor 1
G protein
Conformational change
Online Access:http://www.sciencedirect.com/science/article/pii/S2211383525002977
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 and β-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.
ISSN:2211-3835

Similar Items