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

Background Abnormal glycolysis and lipid synthesis play important roles in the occurrence and development of gastric cancer (GC).Moreover, dysregulation of circadian genes was associated with metabolic reprogramming in the tumor microenvironment. This study aimed to decipher the role of retinoic acid-related orphan receptor alpha (RORα) in glucose and lipid reprogramming of GC. Methods The effects on GC growth in vitro and in vivo were studied using gain- and loss-of-function experiments. Glycolysis and lipid metabolism of GC cells were detected using seahorse assay and test kit. Moreover, regulatory mechanisms underlying RORα deletion were explored using half-life, Co-Immunoprecipitation (Co-IP), Chromatin immunoprecipitation (Chip), luciferase reporter and immunofluorescence co-localization assays in GC cells. In addition, the relationship of RORα with E47 and AKR1A1 was analyzed using clinicopathological retrospective analysis in two cohorts. Results RORα deletion promoted proliferation and 5-FU chemoresistance by enhancing glycolytic activity and lipid synthesis. In contrast, SR1078, a RORα activator, reversed these phenomena and had a synergistic inhibitory effect on cell proliferation through combination with 2-deoxygulose glucose or atorvastatin. Mechanistically, RORα deletion promoted aldo-keto reductase family 1 member A1 (AKR1A1)-induced glycolysis and lipid metabolism to enhance cell proliferation and 5-FU chemoresistance. In detail, the protein stability of the AKR1A1 transcription factor E47 is modulated by β-catenin through binding to form a transcription heterodimer. RORα deletion enhanced wnt3a and β-catenin expression and indirectly inhibited E47 protein stability, leading to attenuated AKR1A1 transcriptional activity. Moreover, AKR1A1 expression was associated with clinicopathological parameters, including age, tumor-node-metastasis stage and tumor grade; AKR1A1 was found to be an independent predictor of GC prognosis and was negatively correlated with RORα expression. Moreover, the disease-free survival time of GC patients with RORα-high/E47-low/AKR1A1-low expression patterns was optimal. Furthermore, RORα, E47 or AKR1A1 expression alone or in combination with each other was associated with response status, the standard uptake value and lipid synthesis. Conclusions These findings revealed a novel mechanism by which RORα regulates glucose and lipid reprogramming and might be a promising target for GC treatment.