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 |
|---|---|
| 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 |
| ResultId |
1 |
|---|---|
| Header |
edsair OpenAIRE edsair.doi.dedup.....7cfa39c2b859cfb32c129f91e1817d6b 806 3 unknown 806.331909179688 |
| PLink |
https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&scope=site&db=edsair&AN=edsair.doi.dedup.....7cfa39c2b859cfb32c129f91e1817d6b&custid=s6537998&authtype=sso |
| FullText |
Array
(
[Availability] => 0
)
|
| Items |
Array
(
[Name] => Title
[Label] => Title
[Group] => Ti
[Data] => A Novel Malate Dehydrogenase 2 Inhibitor Suppresses Hypoxia-Inducible Factor-1 by Regulating Mitochondrial Respiration
)
Array ( [Name] => Author [Label] => Authors [Group] => Au [Data] => <searchLink fieldCode="AR" term="%22Kusik+Jang%22">Kusik Jang</searchLink><br /><searchLink fieldCode="AR" term="%22Hyun+Seung+Ban%22">Hyun Seung Ban</searchLink><br /><searchLink fieldCode="AR" term="%22Bokyung+Kim%22">Bokyung Kim</searchLink><br /><searchLink fieldCode="AR" term="%22Inhyub+Kim%22">Inhyub Kim</searchLink><br /><searchLink fieldCode="AR" term="%22Misun+Won%22">Misun Won</searchLink><br /><searchLink fieldCode="AR" term="%22Kyeong+Lee%22">Kyeong Lee</searchLink><br /><searchLink fieldCode="AR" term="%22Xuezhen+Xu%22">Xuezhen Xu</searchLink> ) Array ( [Name] => TitleSource [Label] => Source [Group] => Src [Data] => PLoS ONE<br />PLOS ONE(11): 9<br />PLoS ONE, Vol 11, Iss 9, p e0162568 (2016) ) Array ( [Name] => Publisher [Label] => Publisher Information [Group] => PubInfo [Data] => Public Library of Science, 2016. ) Array ( [Name] => DatePubCY [Label] => Publication Year [Group] => Date [Data] => 2016 ) Array ( [Name] => Subject [Label] => Subject Terms [Group] => Su [Data] => <searchLink fieldCode="DE" term="%220301+basic+medicine%22">0301 basic medicine</searchLink><br /><searchLink fieldCode="DE" term="%22Vascular+Endothelial+Growth+Factor+A%22">Vascular Endothelial Growth Factor A</searchLink><br /><searchLink fieldCode="DE" term="%22Physiology%22">Physiology</searchLink><br /><searchLink fieldCode="DE" term="%22Cancer+Treatment%22">Cancer Treatment</searchLink><br /><searchLink fieldCode="DE" term="%22lcsh%3AMedicine%22">lcsh:Medicine</searchLink><br /><searchLink fieldCode="DE" term="%22Mitochondrion%22">Mitochondrion</searchLink><br /><searchLink fieldCode="DE" term="%22Biochemistry%22">Biochemistry</searchLink><br /><searchLink fieldCode="DE" term="%22chemistry%2Echemical%5Fcompound%22">chemistry.chemical_compound</searchLink><br /><searchLink fieldCode="DE" term="%22Database+and+Informatics+Methods%22">Database and Informatics Methods</searchLink><br /><searchLink fieldCode="DE" term="%22Mice%22">Mice</searchLink><br /><searchLink fieldCode="DE" term="%220302+clinical+medicine%22">0302 clinical medicine</searchLink><br /><searchLink fieldCode="DE" term="%22Malate+Dehydrogenase%22">Malate Dehydrogenase</searchLink><br /><searchLink fieldCode="DE" term="%22Medicine+and+Health+Sciences%22">Medicine and Health Sciences</searchLink><br /><searchLink fieldCode="DE" term="%22Database+Searching%22">Database Searching</searchLink><br /><searchLink fieldCode="DE" term="%22lcsh%3AScience%22">lcsh:Science</searchLink><br /><searchLink fieldCode="DE" term="%22Hypoxia%22">Hypoxia</searchLink><br /><searchLink fieldCode="DE" term="%22Energy-Producing+Organelles%22">Energy-Producing Organelles</searchLink><br /><searchLink fieldCode="DE" term="%22Glucose+Transporter+Type+1%22">Glucose Transporter Type 1</searchLink><br /><searchLink fieldCode="DE" term="%22Multidisciplinary%22">Multidisciplinary</searchLink><br /><searchLink fieldCode="DE" term="%22Respiration%22">Respiration</searchLink><br /><searchLink fieldCode="DE" term="%22Fatty+Acids%22">Fatty Acids</searchLink><br /><searchLink fieldCode="DE" term="%22Hep+G2+Cells%22">Hep G2 Cells</searchLink><br /><searchLink fieldCode="DE" term="%22Lipids%22">Lipids</searchLink><br /><searchLink fieldCode="DE" term="%22Cell+Hypoxia%22">Cell Hypoxia</searchLink><br /><searchLink fieldCode="DE" term="%22Mitochondria%22">Mitochondria</searchLink><br /><searchLink fieldCode="DE" term="%22Chemistry%22">Chemistry</searchLink><br /><searchLink fieldCode="DE" term="%22Oncology%22">Oncology</searchLink><br /><searchLink fieldCode="DE" term="%22030220+oncology+%26+carcinogenesis%22">030220 oncology & carcinogenesis</searchLink><br /><searchLink fieldCode="DE" term="%22Physical+Sciences%22">Physical Sciences</searchLink><br /><searchLink fieldCode="DE" term="%22Growth+inhibition%22">Growth inhibition</searchLink><br /><searchLink fieldCode="DE" term="%22Cellular+Structures+and+Organelles%22">Cellular Structures and Organelles</searchLink><br /><searchLink fieldCode="DE" term="%22Research+Article%22">Research Article</searchLink><br /><searchLink fieldCode="DE" term="%22Chemical+Elements%22">Chemical Elements</searchLink><br /><searchLink fieldCode="DE" term="%22Signal+Transduction%22">Signal Transduction</searchLink><br /><searchLink fieldCode="DE" term="%22Citric+Acid+Cycle%22">Citric Acid Cycle</searchLink><br /><searchLink fieldCode="DE" term="%22Antineoplastic+Agents%22">Antineoplastic Agents</searchLink><br /><searchLink fieldCode="DE" term="%22Library+Screening%22">Library Screening</searchLink><br /><searchLink fieldCode="DE" term="%22Biology%22">Biology</searchLink><br /><searchLink fieldCode="DE" term="%22Bioenergetics%22">Bioenergetics</searchLink><br /><searchLink fieldCode="DE" term="%22Research+and+Analysis+Methods%22">Research and Analysis Methods</searchLink><br /><searchLink fieldCode="DE" term="%22Malate+dehydrogenase%22">Malate dehydrogenase</searchLink><br /><searchLink fieldCode="DE" term="%2203+medical+and+health+sciences%22">03 medical and health sciences</searchLink><br /><searchLink fieldCode="DE" term="%22Oxygen+Consumption%22">Oxygen Consumption</searchLink><br /><searchLink fieldCode="DE" term="%22Cell+Line%2C+Tumor%22">Cell Line, Tumor</searchLink><br /><searchLink fieldCode="DE" term="%22Animals%22">Animals</searchLink><br /><searchLink fieldCode="DE" term="%22Humans%22">Humans</searchLink><br /><searchLink fieldCode="DE" term="%22Molecular+Biology+Techniques%22">Molecular Biology Techniques</searchLink><br /><searchLink fieldCode="DE" term="%22Molecular+Biology%22">Molecular Biology</searchLink><br /><searchLink fieldCode="DE" term="%22Molecular+Biology+Assays+and+Analysis+Techniques%22">Molecular Biology Assays and Analysis Techniques</searchLink><br /><searchLink fieldCode="DE" term="%22lcsh%3AR%22">lcsh:R</searchLink><br /><searchLink fieldCode="DE" term="%22Glucose+transporter%22">Glucose transporter</searchLink><br /><searchLink fieldCode="DE" term="%22AMPK%22">AMPK</searchLink><br /><searchLink fieldCode="DE" term="%22Biology+and+Life+Sciences%22">Biology and Life Sciences</searchLink><br /><searchLink fieldCode="DE" term="%22Metabolism%22">Metabolism</searchLink><br /><searchLink fieldCode="DE" term="%22Cell+Biology%22">Cell Biology</searchLink><br /><searchLink fieldCode="DE" term="%22Malate+dehydrogenase+2%22">Malate dehydrogenase 2</searchLink><br /><searchLink fieldCode="DE" term="%22HCT116+Cells%22">HCT116 Cells</searchLink><br /><searchLink fieldCode="DE" term="%22Hypoxia-Inducible+Factor+1%2C+alpha+Subunit%22">Hypoxia-Inducible Factor 1, alpha Subunit</searchLink><br /><searchLink fieldCode="DE" term="%22Citric+acid+cycle%22">Citric acid cycle</searchLink><br /><searchLink fieldCode="DE" term="%22Oxygen%22">Oxygen</searchLink><br /><searchLink fieldCode="DE" term="%22030104+developmental+biology%22">030104 developmental biology</searchLink><br /><searchLink fieldCode="DE" term="%22chemistry%22">chemistry</searchLink><br /><searchLink fieldCode="DE" term="%22lcsh%3AQ%22">lcsh:Q</searchLink><br /><searchLink fieldCode="DE" term="%22Physiological+Processes%22">Physiological Processes</searchLink><br /><searchLink fieldCode="DE" term="%22HeLa+Cells%22">HeLa Cells</searchLink> ) Array ( [Name] => Abstract [Label] => Description [Group] => Ab [Data] => 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. ) Array ( [Name] => Language [Label] => Language [Group] => Lang [Data] => English ) Array ( [Name] => ISSN [Label] => ISSN [Group] => ISSN [Data] => 1932-6203 ) Array ( [Name] => URL [Label] => Access URL [Group] => URL [Data] => <link linkTarget="URL" linkTerm="https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7cfa39c2b859cfb32c129f91e1817d6b" linkWindow="_blank">https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7cfa39c2b859cfb32c129f91e1817d6b</link><br /><link linkTarget="URL" linkTerm="http://europepmc.org/articles/PMC5017629" linkWindow="_blank">http://europepmc.org/articles/PMC5017629</link> ) Array ( [Name] => Copyright [Label] => Rights [Group] => Cpyrght [Data] => OPEN ) Array ( [Name] => AN [Label] => Accession Number [Group] => ID [Data] => edsair.doi.dedup.....7cfa39c2b859cfb32c129f91e1817d6b ) |
| RecordInfo |
Array
(
[BibEntity] => Array
(
[Languages] => Array
(
[0] => Array
(
[Text] => English
)
)
[Subjects] => Array
(
[0] => Array
(
[SubjectFull] => 0301 basic medicine
[Type] => general
)
[1] => Array
(
[SubjectFull] => Vascular Endothelial Growth Factor A
[Type] => general
)
[2] => Array
(
[SubjectFull] => Physiology
[Type] => general
)
[3] => Array
(
[SubjectFull] => Cancer Treatment
[Type] => general
)
[4] => Array
(
[SubjectFull] => lcsh:Medicine
[Type] => general
)
[5] => Array
(
[SubjectFull] => Mitochondrion
[Type] => general
)
[6] => Array
(
[SubjectFull] => Biochemistry
[Type] => general
)
[7] => Array
(
[SubjectFull] => chemistry.chemical_compound
[Type] => general
)
[8] => Array
(
[SubjectFull] => Database and Informatics Methods
[Type] => general
)
[9] => Array
(
[SubjectFull] => Mice
[Type] => general
)
[10] => Array
(
[SubjectFull] => 0302 clinical medicine
[Type] => general
)
[11] => Array
(
[SubjectFull] => Malate Dehydrogenase
[Type] => general
)
[12] => Array
(
[SubjectFull] => Medicine and Health Sciences
[Type] => general
)
[13] => Array
(
[SubjectFull] => Database Searching
[Type] => general
)
[14] => Array
(
[SubjectFull] => lcsh:Science
[Type] => general
)
[15] => Array
(
[SubjectFull] => Hypoxia
[Type] => general
)
[16] => Array
(
[SubjectFull] => Energy-Producing Organelles
[Type] => general
)
[17] => Array
(
[SubjectFull] => Glucose Transporter Type 1
[Type] => general
)
[18] => Array
(
[SubjectFull] => Multidisciplinary
[Type] => general
)
[19] => Array
(
[SubjectFull] => Respiration
[Type] => general
)
[20] => Array
(
[SubjectFull] => Fatty Acids
[Type] => general
)
[21] => Array
(
[SubjectFull] => Hep G2 Cells
[Type] => general
)
[22] => Array
(
[SubjectFull] => Lipids
[Type] => general
)
[23] => Array
(
[SubjectFull] => Cell Hypoxia
[Type] => general
)
[24] => Array
(
[SubjectFull] => Mitochondria
[Type] => general
)
[25] => Array
(
[SubjectFull] => Chemistry
[Type] => general
)
[26] => Array
(
[SubjectFull] => Oncology
[Type] => general
)
[27] => Array
(
[SubjectFull] => 030220 oncology & carcinogenesis
[Type] => general
)
[28] => Array
(
[SubjectFull] => Physical Sciences
[Type] => general
)
[29] => Array
(
[SubjectFull] => Growth inhibition
[Type] => general
)
[30] => Array
(
[SubjectFull] => Cellular Structures and Organelles
[Type] => general
)
[31] => Array
(
[SubjectFull] => Research Article
[Type] => general
)
[32] => Array
(
[SubjectFull] => Chemical Elements
[Type] => general
)
[33] => Array
(
[SubjectFull] => Signal Transduction
[Type] => general
)
[34] => Array
(
[SubjectFull] => Citric Acid Cycle
[Type] => general
)
[35] => Array
(
[SubjectFull] => Antineoplastic Agents
[Type] => general
)
[36] => Array
(
[SubjectFull] => Library Screening
[Type] => general
)
[37] => Array
(
[SubjectFull] => Biology
[Type] => general
)
[38] => Array
(
[SubjectFull] => Bioenergetics
[Type] => general
)
[39] => Array
(
[SubjectFull] => Research and Analysis Methods
[Type] => general
)
[40] => Array
(
[SubjectFull] => Malate dehydrogenase
[Type] => general
)
[41] => Array
(
[SubjectFull] => 03 medical and health sciences
[Type] => general
)
[42] => Array
(
[SubjectFull] => Oxygen Consumption
[Type] => general
)
[43] => Array
(
[SubjectFull] => Cell Line, Tumor
[Type] => general
)
[44] => Array
(
[SubjectFull] => Animals
[Type] => general
)
[45] => Array
(
[SubjectFull] => Humans
[Type] => general
)
[46] => Array
(
[SubjectFull] => Molecular Biology Techniques
[Type] => general
)
[47] => Array
(
[SubjectFull] => Molecular Biology
[Type] => general
)
[48] => Array
(
[SubjectFull] => Molecular Biology Assays and Analysis Techniques
[Type] => general
)
[49] => Array
(
[SubjectFull] => lcsh:R
[Type] => general
)
[50] => Array
(
[SubjectFull] => Glucose transporter
[Type] => general
)
[51] => Array
(
[SubjectFull] => AMPK
[Type] => general
)
[52] => Array
(
[SubjectFull] => Biology and Life Sciences
[Type] => general
)
[53] => Array
(
[SubjectFull] => Metabolism
[Type] => general
)
[54] => Array
(
[SubjectFull] => Cell Biology
[Type] => general
)
[55] => Array
(
[SubjectFull] => Malate dehydrogenase 2
[Type] => general
)
[56] => Array
(
[SubjectFull] => HCT116 Cells
[Type] => general
)
[57] => Array
(
[SubjectFull] => Hypoxia-Inducible Factor 1, alpha Subunit
[Type] => general
)
[58] => Array
(
[SubjectFull] => Citric acid cycle
[Type] => general
)
[59] => Array
(
[SubjectFull] => Oxygen
[Type] => general
)
[60] => Array
(
[SubjectFull] => 030104 developmental biology
[Type] => general
)
[61] => Array
(
[SubjectFull] => chemistry
[Type] => general
)
[62] => Array
(
[SubjectFull] => lcsh:Q
[Type] => general
)
[63] => Array
(
[SubjectFull] => Physiological Processes
[Type] => general
)
[64] => Array
(
[SubjectFull] => HeLa Cells
[Type] => general
)
)
[Titles] => Array
(
[0] => Array
(
[TitleFull] => A Novel Malate Dehydrogenase 2 Inhibitor Suppresses Hypoxia-Inducible Factor-1 by Regulating Mitochondrial Respiration
[Type] => main
)
)
)
[BibRelationships] => Array
(
[HasContributorRelationships] => Array
(
[0] => Array
(
[PersonEntity] => Array
(
[Name] => Array
(
[NameFull] => Kusik Jang
)
)
)
[1] => Array
(
[PersonEntity] => Array
(
[Name] => Array
(
[NameFull] => Hyun Seung Ban
)
)
)
[2] => Array
(
[PersonEntity] => Array
(
[Name] => Array
(
[NameFull] => Bokyung Kim
)
)
)
[3] => Array
(
[PersonEntity] => Array
(
[Name] => Array
(
[NameFull] => Inhyub Kim
)
)
)
[4] => Array
(
[PersonEntity] => Array
(
[Name] => Array
(
[NameFull] => Misun Won
)
)
)
[5] => Array
(
[PersonEntity] => Array
(
[Name] => Array
(
[NameFull] => Kyeong Lee
)
)
)
[6] => Array
(
[PersonEntity] => Array
(
[Name] => Array
(
[NameFull] => Xuezhen Xu
)
)
)
)
[IsPartOfRelationships] => Array
(
[0] => Array
(
[BibEntity] => Array
(
[Dates] => Array
(
[0] => Array
(
[D] => 01
[M] => 09
[Type] => published
[Y] => 2016
)
)
[Identifiers] => Array
(
[0] => Array
(
[Type] => issn-print
[Value] => 19326203
)
[1] => Array
(
[Type] => issn-locals
[Value] => edsair
)
[2] => Array
(
[Type] => issn-locals
[Value] => edsairFT
)
)
[Numbering] => Array
(
[0] => Array
(
[Type] => volume
[Value] => 11
)
[1] => Array
(
[Type] => issue
[Value] => 9
)
)
[Titles] => Array
(
[0] => Array
(
[TitleFull] => PLoS ONE
[Type] => main
)
)
)
)
)
)
)
|
| IllustrationInfo |