GPCRs interaction with LGR5: Implications to cancer stemness

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.