CBMS-5 STEAROYL-COA DESATURASE INHIBITOR INDUCES APOPTOSIS VIA ENHANCING LIPOLYSIS IN IDH MUTANT GLIOMA

Abstract

Abstract Background Little is known about the antineoplastic effect and the mechanism of Stearoyl-CoA desaturase (SCD) inhibitor which catalyzes the biosynthesis of monounsaturated fatty acids (MUFA). Mutant isocitrate dehydrogenase (IDH) catalyzes the NADPH-mediated reduction of α-ketoglutarate (αKG) to 2-hydroxyglutarate (2HG) and causes metabolic reprograming of lipid. In this study, to develop a feasible drug for IDH mutant glioma, we have investigated the changes of the lipid distribution and the mechanism of antineoplastic effect of SCD inhibition in IDH mutant glioma. Materials and Methods We prepared genetically engineered glioma cell lines (U251 wild type: U251WT and U251 IDH mutant: U251mut) and patient derived cell lines (TS603 and GSC923). Lipid metabolic analysis was conducted by using Raman imaging spectroscopy and LC-MS, and functional analysis for the role of SCD expression in IDH mutant glioma was investigated by RNA sequence and Western-blotting. Results: In LC-MS analysis of the extracted Endoplasmic Reticulum, MUFAs were distributed significantly higher in IDH mutant than wild type. SCD expression was increased in IDH mutant compared to wild type due to 2HG-mediated upregulation of SCD. Therefore, IDH mutant in which SCD expression level was high indicated high sensitivity to SCD inhibitor, and apoptosis was highly induced in IDH mutant compared to wild type. RNA sequencing was performed in U251mut treated with SCD inhibitor compared to U251mut treated with DMSO, and lipid droplet metabolism-associated RNA expression was significantly changed in U251mut treated with SCD inhibitor. We checked lipid droplet in U251mut 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 2HG produced in IDH mutant glioma directly induces SCD expression and enhances sensitivity to SCD inhibitor, which suggests that SCD inhibitor is an IDH mutant glioma-specific treatment strategy.