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GPCRs interaction with LGR5: Implications to cancer stemness
Jeetendra K Nag1, Ganesh Subedi1,2, Tatyana Rudina3
1Department of Heart, Blood and Kidney Research, Cleveland, Clinic Research, Cleveland, OH 44195 USA.
Abstract:
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.
Insights
G-protein coupled receptors (GPCRs), such as protease-activated receptor 4 (PAR4) and GPR25, stabilize beta-catenin, suggesting a role in regulating cancer stem cell (CSC) niches. These findings offer potential therapeutic targets for CSCs.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- G-protein coupled receptors (GPCRs) play a crucial role in tumor biology.
- The involvement of GPCRs in the cancer stem cell (CSC) niche remains largely unknown.
- Understanding CSC mechanisms is vital for developing effective cancer therapies.
Purpose of the Study:
- To investigate the role of specific GPCRs in regulating the CSC niche.
- To elucidate the molecular mechanisms by which GPCRs influence CSC properties.
Main Methods:
- Western blotting
- Co-immunoprecipitation (co-IP)
- RT-PCR
- Lef/Tcf luciferase activity assays
- Protein-protein docking analyses (Alpha Fold3 HANDDOCK v2.4)
Main Results:
- Protease-activated receptor 4 (PAR4) was shown to induce beta-catenin levels and associate with the LRP6 coreceptor.
- PAR4 promotes DVL nuclear translocation, leading to enhanced beta-catenin transcriptional activity and downstream target gene expression.
- Both PAR4 and GPR25 were found to co-bind with leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5), a known marker associated with stem cells.
Conclusions:
- GPCRs, including PAR4 and GPR25, can stabilize beta-catenin and co-link with LGR5.
- GPCRs that induce beta-catenin stabilization are potentially involved in regulating the CSC niche.
- These findings suggest novel therapeutic strategies targeting GPCRs for controlling CSC populations.
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