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- W4377029079 abstract "<b>Abstract ID 18095</b> <b>Poster Board 38</b> <b>Aims:</b> Kirsten Rat Sarcoma virus (KRAS) oncogene, found in 20-25% of lung cancer patients, regulates metabolic reprogramming and redox status during tumorigenesis. Recently, histone deacetylase (HDAC) inhibitors are widely investigated for the treatment of KRAS-mutant lung cancer. In the current study, we investigate the effect of HDAC inhibitor (HDACi) belinostat on nuclear factor erythroid 2-related factor 2 (NRF2) and mitochondrial metabolism for the treatment of KRAS-mutant cell lung cancer. <b>Main methods:</b> LC-MS metabolomic study of belinostat on mitochondrial metabolism was performed in KRAS-mutant non-small cell lung cancer cells. Furthermore, L-methionine (methyl-<sup>13</sup>C) isotope tracer was used to explore the effect of the belinostat in one carbon metabolism. Bioinformatic analyses were performed with the metabolomic data to identify the pattern of the significantly regulated metabolites. To study the effect of belinostat on redox signaling Are-NRF2 pathway, luciferase reporter activity assay was done in stably transfected HepG2-C8 cells (containing pARE-TI-luciferase construct), followed by qPCR analysis of NRF2 and its target gene in NSCLC cells. <b>Key findings:</b> Metabolomic study revealed significantly altered metabolic levels related to redox homeostasis including tricarboxylic acid (TCA) cycle metabolites (citrate, aconitate, fumarate, malate and α-ketoglutarate); urea cycle metabolites (Arginine, ornithine, argino-succinate, aspartate and fumarate); and glutathione metabolism pathway (GSH/GSSG and NAD/NADH ratio) after belinostat treatment. <sup>13</sup>C stable isotope labeling data indicates potential role of belinostat in creatine biosynthesis via methylation of guanidinoacetate. Moreover, belinostat inhibited NRF2 activity and downregulated the expression of NRF2 and its target gene NAD(P)H:quinone oxidoreductase 1 (NQO1). <b>Significance:</b> Belinostat is effective in killing KRAS-mutant lung cancer cells by regulating mitochondrial metabolism. <b>Keywords:</b> Belinostat; HDAC inhibitor; Mitochondrial metabolism; KRAS mutation; NRF2; Lung cancer This work was supported in part by institutional funds and and P30 ES005022 from the National Institute of Environmental Health Sciences (NIEHS)." @default.
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- W4377029079 date "2023-05-18" @default.
- W4377029079 modified "2023-09-29" @default.
- W4377029079 title "Histone Deacetylase Inhibitor Belinostat Regulates Metabolic Reprogramming in Killing Kras-Mutant Human Lung Cancer Cells" @default.
- W4377029079 doi "https://doi.org/10.1124/jpet.122.180950" @default.
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