Endoplasmic Reticulum stress-dependent expression of ERO1L promotes aerobic glycolysis in Pancreatic Cancer

Rationale: Endoplasmic reticulum oxidoreductase 1 alpha (EROIL) is an endoplasmic reticulum (ER) luminal glycoprotein that has a role in the formation of disulfide bonds of secreted proteins and membrane proteins. Emerging data identify EROIL as a tumor promoter in a wide spectrum of human malignancies. However, its molecular basis of oncogenic activities remains largely unknown. Methods: Pan-cancer analysis was performed to determine the expression profile and prognostic value of EROIL in human cancers. The mechanism by which EROIL promotes tumor growth and glycolysis in pancreatic ductal adenocarcinoma (PDAC) was investigated by cell biological, molecular, and biochemical approaches. Results: EROIL was highly expressed in PDAC and its precursor pancreatic intraepithelial neoplasia and acts as an independent prognostic factor for patient survival. Hypoxia and ER stress contributed to the overexpression pattern of EROIL in PDAC. EROIL knockdown or pharmacological inhibition with EN460 suppressed PDAC cell proliferation in vitro and slowed tumor growth in vivo. Ectopic expression of wild type EROIL but not its inactive mutant form EROL-C394A promoted tumor growth. Bioinformatics analyses and functional analyses confirmed a regulatory role of EROIL on the Warburg effect. Notably, inhibition of tumor glycolysis partially abrogated the growth-promoting activity of EROIL. Mechanistically, EROIL-mediated ROS generation was essential for its oncogenic activities. In clinical samples, EROIL expression was correlated with the maximum standard uptake value (SUVmax) in PDAC patients who received F-18-FDG PET/CT imaging preoperatively. Analysis of TCGA cohort revealed a specific glycolysis gene expression signature that is highly correlated with unfolded protein response-related gene signature. Conclusion: Our findings uncover a key function for EROIL in Warburg metabolism and indicate that targeting this pathway may offer alternative therapeutic strategies for PDAC.