ORMDL2 Promotes the Growth of Glioma through mTORC1-Mediated Fatty Acid Metabolism.

Fatty acid metabolism is critical for numerous biological processes involved in the pathogenesis of glioma. This study aimed to survey the role of ORMDL sphingolipid biosynthesis regulator 2 (ORMDL2) in fatty acid metabolism of glioma cells. The expression of ORMDL2 in glioma and its association with survival rate was detected using The Cancer Genome Atlas (TCGA) data and Kaplan-Meier survival curve. The effect of ORMDL2 on glioma was explored by culturing human glioma cells in vitro and constructing mouse glioma models. Cell proliferation, apoptosis, and fatty acid metabolism were detected by CCK-8, flow cytometry, colony formation assay, BODIPY staining, immunohistochemistry, western blotting, and qRT-PCR. ORMDL2 was upregulated in lower-grade glioma (LGG) and glioblastoma multiforme (GBM) tissues as compared to brain tissues collected from patients with traumatic craniotomy. Its high expression was associated with poor patient survival. ORMDL2 silencing inhibited glioma cell proliferation, lipid droplet formation, and promoted apoptosis in vitro. Silencing of ORMDL2 in xenograft mouse model inhibited tumor volume and weight. Additionally, ORMDL2 silencing decreased the levels of fatty acid metabolism-related factors FASN, ACC1 and SCD1, and the phosphorylation of a downstream effector of mTORC1 (S6K). Moreover, mTORC1 agonist MHY1485 reversed the inhibitory effect of ORMDL2 silencing on U87 cell fatty acid metabolism; mTORC1 inhibitor rapamycin reversed the promoting effect of ORMDL2 overexpression on U251 cell fatty acid metabolism. To conclude, this study demonstrated the high expression of ORMDL2 in glioma and its tumor-promoting action by activating mTORC1-mediated fatty acid metabolism.