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.
10.1016/j.apsb.2025.04.030
- Author:
Yunjun GE
1
;
Huiwen GUAN
1
;
Ting LI
2
;
Jie WANG
1
;
Liang YING
1
;
Shuhui GUO
3
;
Jinjian LU
2
;
Richard D YE
4
;
Guosheng WU
1
Author Information
1. Department of Basic Medical Science, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, China; MoE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, School of Medicine, Wuxi 214122, China.
2. State Key Laboratory for Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau SAR 999078, China.
3. Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518172, China.
4. Kobilka Institute of Innovative Drug Discovery, School of Medicine, the Chinese University of Hong Kong, Shenzhen 518172, China.
- Publication Type:Journal Article
- Keywords:
Biased agonist;
Conformational change;
Formyl peptide receptor 1;
G protein;
G protein-coupled receptor;
Signaling pathway;
Therapeutic strategy;
Yersinia LcrV
- From:
Acta Pharmaceutica Sinica B
2025;15(7):3646-3662
- CountryChina
- Language:English
-
Abstract:
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.
