A Novel Malate Dehydrogenase 2 Inhibitor Suppresses Hypoxia-Inducible Factor-1 by Regulating Mitochondrial Respiration
| العنوان: | A Novel Malate Dehydrogenase 2 Inhibitor Suppresses Hypoxia-Inducible Factor-1 by Regulating Mitochondrial Respiration |
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| المؤلفون: | Kusik Jang, Hyun Seung Ban, Bokyung Kim, Inhyub Kim, Misun Won, Kyeong Lee, Xuezhen Xu |
| المصدر: | PLoS ONE PLOS ONE(11): 9 PLoS ONE, Vol 11, Iss 9, p e0162568 (2016) |
| بيانات النشر: | Public Library of Science, 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | 0301 basic medicine, Vascular Endothelial Growth Factor A, Physiology, Cancer Treatment, lcsh:Medicine, Mitochondrion, Biochemistry, chemistry.chemical_compound, Database and Informatics Methods, Mice, 0302 clinical medicine, Malate Dehydrogenase, Medicine and Health Sciences, Database Searching, lcsh:Science, Hypoxia, Energy-Producing Organelles, Glucose Transporter Type 1, Multidisciplinary, Respiration, Fatty Acids, Hep G2 Cells, Lipids, Cell Hypoxia, Mitochondria, Chemistry, Oncology, 030220 oncology & carcinogenesis, Physical Sciences, Growth inhibition, Cellular Structures and Organelles, Research Article, Chemical Elements, Signal Transduction, Citric Acid Cycle, Antineoplastic Agents, Library Screening, Biology, Bioenergetics, Research and Analysis Methods, Malate dehydrogenase, 03 medical and health sciences, Oxygen Consumption, Cell Line, Tumor, Animals, Humans, Molecular Biology Techniques, Molecular Biology, Molecular Biology Assays and Analysis Techniques, lcsh:R, Glucose transporter, AMPK, Biology and Life Sciences, Metabolism, Cell Biology, Malate dehydrogenase 2, HCT116 Cells, Hypoxia-Inducible Factor 1, alpha Subunit, Citric acid cycle, Oxygen, 030104 developmental biology, chemistry, lcsh:Q, Physiological Processes, HeLa Cells |
| الوصف: | We previously reported that hypoxia-inducible factor (HIF)-1 inhibitor LW6, an aryloxyacety-lamino benzoic acid derivative, inhibits malate dehydrogenase 2 (MDH2) activity during the mitochondrial tricarboxylic acid (TCA) cycle. In this study, we present a novel MDH2 inhibitor compound 7 containing benzohydrazide moiety, which was identified through structure-based virtual screening of chemical library. Similar to LW6, compound 7 inhibited MDH2 activity in a competitive fashion, thereby reducing NADH level. Consequently, compound 7 reduced oxygen consumption and ATP production during the mitochondrial respiration cycle, resulting in increased intracellular oxygen concentration. Therefore, compound 7 suppressed the accumulation of HIF-1 alpha and expression of its target genes, vascular endothelial growth factor (VEGF) and glucose transporter 1 (GLUT1). Moreover, reduction in ATP content activated AMPK, thereby inactivating ACC and mTOR the downstream pathways. As expected, compound 7 exhibited significant growth inhibition of human colorectal cancer HCT116 cells. Compound 7 demonstrated substantial anti-tumor efficacy in an in vivo xenograft assay using HCT116 mouse model. Taken together, a novel MDH2 inhibitor, compound 7, suppressed HIF-1 alpha accumulation via reduction of oxygen consumption and ATP production, integrating metabolism into anti-cancer efficacy in cancer cells. |
| اللغة: | English |
| تدمد: | 1932-6203 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7cfa39c2b859cfb32c129f91e1817d6bTest http://europepmc.org/articles/PMC5017629Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....7cfa39c2b859cfb32c129f91e1817d6b |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19326203 |
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