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

Abstract

Rationale: Endoplasmic reticulum oxidoreductase 1 alpha (ERO1L) 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 ERO1L 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 ERO1L in human cancers. The mechanism by which ERO1L promotes tumor growth and glycolysis in pancreatic ductal adenocarcinoma (PDAC) was investigated by cell biological, molecular, and biochemical approaches. Results: ERO1L 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 ERO1L in PDAC. ERO1L knockdown or pharmacological inhibition with EN460 suppressed PDAC cell proliferation in vitro and slowed tumor growth in vivo . Ectopic expression of wild type ERO1L but not its inactive mutant form EROL-C394A promoted tumor growth. Bioinformatics analyses and functional analyses confirmed a regulatory role of ERO1L on the Warburg effect. Notably, inhibition of tumor glycolysis partially abrogated the growth-promoting activity of ERO1L. Mechanistically, ERO1L-mediated ROS generation was essential for its oncogenic activities. In clinical samples, ERO1L expression was correlated with the maximum standard uptake value (SUVmax) in PDAC patients who received 18 F-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 ERO1L in Warburg metabolism and indicate that targeting this pathway may offer alternative therapeutic strategies for PDAC.

Targeting hypoxic tumor microenvironment in pancreatic cancer

“…Treatment with glutathione (GSH) inhibitors results in a significant increase in ROS levels and a transient upregulation in glycolysis in PDAC cells. However, this treatment does not augment ROS-mediated long-term promotion of cell proliferation upon hypoxia-activated ERO1L overexpression, suggesting that high ROS levels may induce an oxidative stress in PDAC cells and ultimately decrease cell viability [ 73 ]. ROS generation is induced in a HIF-1α-independent manner under hypoxic conditions [ 74 ], but increased ROS is responsible for HIF-1α stabilization [ 75 , 76 ].…”

Long Noncoding RNA MIR210HG Promotes the Warburg Effect and Tumor Growth by Enhancing HIF-1α Translation in Triple-Negative Breast Cancer

“…Highly proliferative cancer cells preferentially metabolize glucose by aerobic glycolysis rather than through the more energetically efficient oxidative phosphorylation, even in the presence of sufficient oxygen, a phenomenon known as the Warburg effect ( 24 , 25 ). Accumulating evidence suggests that the Warburg effect is closely associated with a poor clinical outcome and exerts critical implications on tumor progression ( 26 , 27 ). In this study, we first performed integrated analysis to characterize hypoxia-related lncRNAs in TNBC through leveraging large-scale TNBC molecular profiles from The Cancer Genome Atlas (TCGA).…”

ERO1L Promotes Hepatic Metastasis through Activating Epithelial-Mesenchymal Transition (EMT) in Pancreatic Cancer

“…To confirm the role of ERO1L in pancreatic cancer migration and invasion, we downregulated ERO1L in the indicated pancreatic cells using shRNAs [ 10 ]. Two PDAC cell lines with relatively higher ERO1L expression, Capan-2 and MiaPaca-2 cells, were selected for loss-of-function study.…”

“…Two PDAC cell lines with relatively higher ERO1L expression, Capan-2 and MiaPaca-2 cells, were selected for loss-of-function study. Stable expression of two short hairpin RNA (sh-1, sh-2) targeting ERO1L resulted in >80% decrease in ERO1L expression of Capan-2 and MiaPaca-2 cells [ 10 ]. The transwell assay without coated Matrigel suggested that ERO1L knockdown significantly inhibited pancreatic cancer cell migration ( Figure 2(a) ), whereas the transwell assay with coated Matrigel suggested that ERO1L knockdown significantly suppressed pancreatic cancer cell invasion ( Figure 2(b) ).…”