REG3A promotes gemcitabine resistance in pancreatic cancer via the GPR54/ARRB2/ERK1/2 ligand-directed signaling pathway

Gemcitabine is a widely employed first-line chemotherapeutic drug for pancreatic cancer (PCa). However, the rapid emergence of gemcitabine resistance poses a major clinical hurdle. Here, we identified REG3A as a crucial determinant of poor prognosis in PCa. Notably, REG3A was upregulated in tumor tissues from clinical gemcitabine-resistant PCa patients. Through comprehensive in vitro cellular assays and in vivo studies using Reg3g (the murine homolog of REG3A) knockout mice, we demonstrated that REG3A deficiency sensitized PCa to gemcitabine treatment. Mechanistically, RNA sequencing (RNA-Seq) combined with Protein-Protein Interaction (PPI) analysis revealed that REG3A functioned as an exocytosis protein binds to the novel membrane receptor GPR54. The interaction increased membrane localization of GPR54, which subsequently engaged ARRB2 as a scaffolding molecule, leading to activation of the ERK1/2 pathway and suppression of gemcitabine-induced apoptosis. Moreover, the GPR54 agonist KP10 synergistically enhanced gemcitabine resistance in conjunction with REG3A, while interference with GPR54 or its antagonist KP234 attenuated REG3A-induced gemcitabine resistance. Targeting REG3A or pharmacologically inhibiting its downstream signaling molecules may represent a promising strategy to overcome gemcitabine resistance. Overall, REG3A could serve as a potential biomarker for gemcitabine resistance in PCa, offering a new avenue for therapeutic intervention and patient stratification.