TMET-59. Adipokine metabolic signaling in IDH1 R132H mutant low-grade gliomas

Abstract INTRODUCTION Low-grade gliomas (LGGs), classified as WHO Grade 2 tumors, are defined by mutations in isocitrate dehydrogenase (IDH). IDH R132H is the most common mutation in LGGs and promotes the conversion of alpha ketoglutarate to 2-hydroxyglutarate (2-HG), which alters lipid metabolism and redox balance. Our group has previously demonstrated that LGG cells harboring the IDH1 R132H mutation are resistant to ferroptosis, a regulated form of cell death driven by oxidative stress. This resistance may be influenced by chemerin, a lipid-signaling adipokine implicated in lipid metabolism and tumor progression in multiple cancer types. However, the role of chemerin in LGG progression and its potential interaction with 2-HG has not been explored. METHODS Mouse glioma cell lines expressing either IDH1 wild-type or IDH1 R132H were serially transplanted into immunocompetent mice to produce the C266-6 (wild-type) and C266-2 (IDH1 mutant) cell lines. Chemerin levels were evaluated via ELISA, RT-qPCR, and Western blotting at baseline and after exogenous administration of 2-HG. Cell viability assays were conducted to assess ferroptosis sensitivity. RESULTS Analysis of the Cancer Genome Atlas (TCGA) database showed that elevated chemerin expression in LGGs correlates with worse overall survival. IDH1 R132H-mutant cells exhibited significantly higher chemerin secretion and protein levels (p < 0.01), along with increased RARRES2 (i.e. chemerin) mRNA levels in vitro. No change in chemerin levels was detected with 2-HG administration after 24 hours. Interestingly, RARRES2 mRNA levels and chemerin protein expression increased when LGG cells were placed under oxidative stress through GPX4 inhibition and reduced glutathione synthesis. CONCLUSION Our results show chemerin is associated with worse patient outcomes and may be upregulated in IDH1-mutant glioma models in vitro. While no relationship was found between chemerin and 2-HG, chemerin may be modulated by ferroptosis and oxidative stress in LGGs.