RORα inhibits proliferation and chemoresistance through AKR1A1-induced glucose and lipid reprogramming in gastric cancer

Background: Abnormal glycolysis and lipid metabolism play important roles in the occurrence and development of gastric cancer (GC). Moreover, dysregulation of circadian genes is associated with metabolic reprogramming in the tumor microenvironment. This study aimed to determine the role of retinoic acid-related orphan receptor alpha (ROR alpha) in glucose and lipid reprogramming in GC. Methods: The effects on cell proliferation and chemoresistance in vitro and in vivo were studied using gain- and loss-of-function experiments. Glycolytic activity and lipid synthesis were assessed using a Seahorse assay and reagent kits. Moreover, the regulatory mechanisms were explored using half-life, coimmunoprecipitation (Co-IP), chromatin immunoprecipitation (ChIP), luciferase reporter and immunofluorescence colocalization assays in GC cells. In addition, the relationships of ROR alpha with E47 and AKR1A1 were analyzed using public databases and retrospective clinicopathological analyses. Results: ROR alpha deletion promoted cell proliferation and fluorouracil (5-FU) chemoresistance by increasing glycolytic activity and lipid synthesis. In contrast, SR1078, an ROR alpha activator, reversed these changes and had a synergistic inhibitory effect on cell proliferation in combination with 2-deoxygulose glucose (2-DG) or atorvastatin. Mechanistically, aldo-keto reductase family 1 member A1 (AKR1A1), is the key driver of ROR alpha mediated glucose and lipid reprogramming. Specifically, E47 is an AKR1A1 transcription factor, and its stability is affected by beta-catenin. ROR alpha deletion indirectly promoted E47 protein stability through the up-regulation of beta-catenin, leading to increased AKR1A1 transcriptional activity. Moreover, ROR alpha, E47 and AKR1A1 expression was dysregulated, and associated with clinicopathological parameters and prognosis in patients with GC. These expression patterns including ROR alpha-low, E47-high and AKR1A1-high expression patterns alone or in combination were correlated with reduced responsiveness, poor prognosis, increased standard uptake value (SUV) levels and lipid droplet formation. Conclusions: These findings reveal a novel mechanism by which ROR alpha regulates glucose and lipid reprogramming and may be a promising target for GC treatment.