Journal of Cancer · 2026
GPCRs interaction with LGR5: Implications to cancer stemness.
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Nag Jeetendra K, Subedi Ganesh, Rudina Tatyana, Bar-Shavit Rachel
Аннотация
UNLABELLED: Background/Objectives: The central role of G-protein coupled receptors (GPCRs) in tumor biology is becoming acknowledged. Yet their involvement in cancer stem cells (CSCs) niche is unknown. Molecular mechanisms of CSCs allow self-formation capacity, resistance to chemotherapy and immune therapy.
METHODS: Western blots, Co-immunoprecipitation (co-IP) analysis, RT-PCR, Lef/Tcf luciferase activity and Alpha Fold3 HANDDOCK v2.4 protein-protein docking interactions.
RESULTS: It is demonstrated that protease-activated receptor 4 (PAR4) induces β-catenin levels, co-associates with LRP6 coreceptor and promotes DVL nuclear translocation. PAR4 induced β-catenin transcriptional activity is shown by TOPflash luciferase assay and enhanced downstream target genes levels. Significantly, PAR4 co-binds leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) as determined by co-IP and protein-protein docking analyses. We show also that another GPCR namely, GPR25 specifically expressed in the gastrointestinal tract cells, elicits β-catenin stabilization and co associates with LGR5.
CONCLUSIONS: As was previously shown for PAR2 also PAR4 and GPR25 elicit β-catenin stabilization and they co-link with LGR5. We propose that GPCRs that potently induce β-catenin stabilization are potentially involved in the regulation of CSCs niche. Our data may provide future directions for potential partners in the cancer stem cell niche.
METHODS: Western blots, Co-immunoprecipitation (co-IP) analysis, RT-PCR, Lef/Tcf luciferase activity and Alpha Fold3 HANDDOCK v2.4 protein-protein docking interactions.
RESULTS: It is demonstrated that protease-activated receptor 4 (PAR4) induces β-catenin levels, co-associates with LRP6 coreceptor and promotes DVL nuclear translocation. PAR4 induced β-catenin transcriptional activity is shown by TOPflash luciferase assay and enhanced downstream target genes levels. Significantly, PAR4 co-binds leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) as determined by co-IP and protein-protein docking analyses. We show also that another GPCR namely, GPR25 specifically expressed in the gastrointestinal tract cells, elicits β-catenin stabilization and co associates with LGR5.
CONCLUSIONS: As was previously shown for PAR2 also PAR4 and GPR25 elicit β-catenin stabilization and they co-link with LGR5. We propose that GPCRs that potently induce β-catenin stabilization are potentially involved in the regulation of CSCs niche. Our data may provide future directions for potential partners in the cancer stem cell niche.