Subcellular Redistribution of Endomembrane GPR15 Promotes NAD+-Mediated Metabolic Reprogramming and Boosts 5-FU...

Area of Science:

• Oncology
• Cell Biology
• Metabolic Pathways

Background:

• G protein-coupled receptors (GPCRs) exhibit organelle-specific roles in cancer.
• Understanding GPCR subcellular localization is crucial for targeted cancer therapies.

Purpose of the Study:

• To investigate the role of Golgi-localized GPR15 in colorectal cancer chemosensitivity.
• To elucidate the mechanisms of GPR15 trafficking and its impact on metabolic pathways.

Main Methods:

• Investigated GPR15 spatiotemporal trafficking in colorectal cancer cells.
• Assessed the impact of GPR15 on NAD+ levels and metabolic reprogramming.
• Utilized patient-derived organoids and xenograft models for in vivo validation.

Main Results:

• Golgi-localized GPR15 enhances sensitivity to 5-fluorouracil (5-FU) via Gαq-dependent PARP4 inhibition.
• GPR15 trafficking to mitochondria, mediated by MGST1, increases mitochondrial NAD+ abundance.
• This metabolic perturbation primes tumors for 5-FU cytotoxicity, potentiated by PARP inhibitors like rucaparib.

Conclusions:

• Spatially regulated GPCR signaling is a druggable target for enhancing chemotherapy.
• Intracellular receptor trafficking modulates metabolic plasticity, offering novel therapeutic strategies in cancer.