TMET-03. STEAROYL-COA DESATURASE INHIBITOR SUPPRESSES IDH MUTANT GLIOMA GROWTH VIA ENHANCING LIPOLYSIS

Abstract

Abstract BACKGROUND Mutant isocitrate dehydrogenase (IDH) produces 2-hydroxyglutarate (D2HG) and causes metabolic reprograming, but so far, little is known about the role of mutant IDH and D2HG in de novo lipogenesis and fatty acids synthesis. In this study, to develop a feasible drug for IDH mutant glioma, we targeted Stearoyl-CoA desaturase 1 (SCD1) catalyzing the biosynthesis of monosaturated fatty acids (MUFA) to suppress IDH mutant glioma progression. Materials and METHODS We prepared genetically engineered glioma cell lines (U251 wild type: U251WT and U251 IDHR132H mutant: U251RH), normal human astrocytes (empty vector induced-NHA: NHAEV and IDHR132H mutant: NHARH) and patient derived cell lines. Lipid metabolic analysis was conducted by using LC-MS, and functional analysis for the role of SCD1 expression was investigated by RNA sequence and Western-blotting. RESULTS LC-MS analysis of extracted Endoplasmic Reticulum revealed that there was significantly higher amount of MUFA in IDH mutant than wild type. SCD1 expression was increased in IDH mutant compared to wild type due to D2HG-mediated upregulation of SCD1 in IDH mutant. Therefore, IDH mutant in which SCD1 expression level was higher than wild type indicated high sensitivity to SCD inhibitor, and apoptosis was highly induced in IDH mutant compared to wild type. RNA sequencing was performed in U251RH treated with SCD inhibitor compared to U251RH treated with DMSO, and lipid droplet metabolism-associated RNA expression was significantly changed in SCD inhibitor-treated U251RH. Based on the RNA sequence data, we checked lipid droplet in U251RH with presence or absence of SCD inhibitor, and lipolysis was induced by SCD inhibitor treatment, suggesting that SCD inhibition is associated with the apoptosis in IDH mutant via enhanced lipolysis mechanism. CONCLUSIONS D2HG produced in IDH mutant glioma directly induces SCD1 expression and enhances sensitivity to SCD inhibitor, which suggests that SCD inhibitor would be IDH mutant glioma-specific treatment strategy.