In vitro antiglioma action of indomethacin is mediated via AMP-activated protein kinase/mTOR complex 1 signalling pathway.
Identifieur interne : 000815 ( Main/Exploration ); précédent : 000814; suivant : 000816In vitro antiglioma action of indomethacin is mediated via AMP-activated protein kinase/mTOR complex 1 signalling pathway.
Auteurs : Aleksandar Pantovic [Serbie] ; Mihajlo Bosnjak [Serbie] ; Katarina Arsikin [Serbie] ; Milica Kosic [Serbie] ; Milos Mandic [Serbie] ; Biljana Ristic [Serbie] ; Jelena Tosic [Serbie] ; Danica Grujicic [Serbie] ; Aleksandra Isakovic [Serbie] ; Nikola Micic [Serbie] ; Vladimir Trajkovic [Serbie] ; Ljubica Harhaji-Trajkovic [Serbie]Source :
- The international journal of biochemistry & cell biology [ 1878-5875 ] ; 2017.
Descripteurs français
- KwdFr :
- AMP (métabolisme), AMP-Activated Protein Kinases (antagonistes et inhibiteurs), AMP-Activated Protein Kinases (génétique), AMP-Activated Protein Kinases (métabolisme), Adénosine triphosphate (métabolisme), Apoptose (effets des médicaments et des substances chimiques), Calcium (métabolisme), Complexe-1 cible mécanistique de la rapamycine (MeSH), Complexes multiprotéiques (antagonistes et inhibiteurs), Complexes multiprotéiques (métabolisme), Glioblastome (métabolisme), Glioblastome (traitement médicamenteux), Gliome (anatomopathologie), Gliome (métabolisme), Gliome (traitement médicamenteux), Humains (MeSH), Indométacine (pharmacologie), Inhibiteurs des cyclooxygénases (pharmacologie), Lignée cellulaire tumorale (MeSH), Modèles biologiques (MeSH), Petit ARN interférent (génétique), Points de contrôle du cycle cellulaire (effets des médicaments et des substances chimiques), Survie cellulaire (effets des médicaments et des substances chimiques), Sérine-thréonine kinases TOR (antagonistes et inhibiteurs), Sérine-thréonine kinases TOR (métabolisme), Transduction du signal (effets des médicaments et des substances chimiques).
- MESH :
- anatomopathologie : Gliome.
- antagonistes et inhibiteurs : AMP-Activated Protein Kinases, Complexes multiprotéiques, Sérine-thréonine kinases TOR.
- effets des médicaments et des substances chimiques : Apoptose, Points de contrôle du cycle cellulaire, Survie cellulaire, Transduction du signal.
- génétique : AMP-Activated Protein Kinases, Petit ARN interférent.
- métabolisme : AMP, AMP-Activated Protein Kinases, Adénosine triphosphate, Calcium, Complexes multiprotéiques, Glioblastome, Gliome, Sérine-thréonine kinases TOR.
- pharmacologie : Indométacine, Inhibiteurs des cyclooxygénases.
- traitement médicamenteux : Glioblastome, Gliome.
- Complexe-1 cible mécanistique de la rapamycine, Humains, Lignée cellulaire tumorale, Modèles biologiques.
English descriptors
- KwdEn :
- AMP-Activated Protein Kinases (antagonists & inhibitors), AMP-Activated Protein Kinases (genetics), AMP-Activated Protein Kinases (metabolism), Adenosine Monophosphate (metabolism), Adenosine Triphosphate (metabolism), Apoptosis (drug effects), Calcium (metabolism), Cell Cycle Checkpoints (drug effects), Cell Line, Tumor (MeSH), Cell Survival (drug effects), Cyclooxygenase Inhibitors (pharmacology), Glioblastoma (drug therapy), Glioblastoma (metabolism), Glioma (drug therapy), Glioma (metabolism), Glioma (pathology), Humans (MeSH), Indomethacin (pharmacology), Mechanistic Target of Rapamycin Complex 1 (MeSH), Models, Biological (MeSH), Multiprotein Complexes (antagonists & inhibitors), Multiprotein Complexes (metabolism), RNA, Small Interfering (genetics), Signal Transduction (drug effects), TOR Serine-Threonine Kinases (antagonists & inhibitors), TOR Serine-Threonine Kinases (metabolism).
- MESH :
- chemical , antagonists & inhibitors : AMP-Activated Protein Kinases, Multiprotein Complexes, TOR Serine-Threonine Kinases.
- chemical , genetics : AMP-Activated Protein Kinases, RNA, Small Interfering.
- chemical , metabolism : AMP-Activated Protein Kinases, Adenosine Monophosphate, Adenosine Triphosphate, Calcium, Multiprotein Complexes, TOR Serine-Threonine Kinases.
- drug effects : Apoptosis, Cell Cycle Checkpoints, Cell Survival, Signal Transduction.
- drug therapy : Glioblastoma, Glioma.
- metabolism : Glioblastoma, Glioma.
- pathology : Glioma.
- chemical , pharmacology : Cyclooxygenase Inhibitors, Indomethacin.
- Cell Line, Tumor, Humans, Mechanistic Target of Rapamycin Complex 1, Models, Biological.
Abstract
We investigated the role of the intracellular energy-sensing AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway in the in vitro antiglioma effect of the cyclooxygenase (COX) inhibitor indomethacin. Indomethacin was more potent than COX inhibitors diclofenac, naproxen, and ketoprofen in reducing the viability of U251 human glioma cells. Antiglioma effect of the drug was associated with p21 increase and G2M cell cycle arrest, as well as with oxidative stress, mitochondrial depolarization, caspase activation, and the induction of apoptosis. Indomethacin increased the phosphorylation of AMPK and its targets Raptor and acetyl-CoA carboxylase (ACC), and reduced the phosphorylation of mTOR and mTOR complex 1 (mTORC1) substrates p70S6 kinase and PRAS40 (Ser183). AMPK knockdown by RNA interference, as well as the treatment with the mTORC1 activator leucine, prevented indomethacin-mediated mTORC1 inhibition and cytotoxic action, while AMPK activators metformin and AICAR mimicked the effects of the drug. AMPK activation by indomethacin correlated with intracellular ATP depletion and increase in AMP/ATP ratio, and was apparently independent of COX inhibition or the increase in intracellular calcium. Finally, the toxicity of indomethacin towards primary human glioma cells was associated with the activation of AMPK/Raptor/ACC and subsequent suppression of mTORC1/S6K. By demonstrating the involvement of AMPK/mTORC1 pathway in the antiglioma action of indomethacin, our results support its further exploration in glioma therapy.
DOI: 10.1016/j.biocel.2016.12.007
PubMed: 27988363
Affiliations:
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Immunology, School of Medicine, University of Belgrade, Dr. Subotica 1, 11000 Belgrade, Serbia. Electronic address: vtrajkovic@med.bg.ac.rs.</nlm:affiliation><country xml:lang="fr">Serbie</country><wicri:regionArea>Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Dr. Subotica 1, 11000 Belgrade</wicri:regionArea><wicri:noRegion>11000 Belgrade</wicri:noRegion></affiliation></author><author><name sortKey="Harhaji Trajkovic, Ljubica" sort="Harhaji Trajkovic, Ljubica" uniqKey="Harhaji Trajkovic L" first="Ljubica" last="Harhaji-Trajkovic">Ljubica Harhaji-Trajkovic</name><affiliation wicri:level="1"><nlm:affiliation>Institute for Biological Research "Sinisa Stankovic", University of Belgrade, Despot Stefan Blvd. 142, 11000 Belgrade, Serbia. Electronic address: buajk@yahoo.com.</nlm:affiliation><country xml:lang="fr">Serbie</country><wicri:regionArea>Institute for Biological Research "Sinisa Stankovic", University of Belgrade, Despot Stefan Blvd. 142, 11000 Belgrade</wicri:regionArea><wicri:noRegion>11000 Belgrade</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2017">2017</date><idno type="RBID">pubmed:27988363</idno><idno type="pmid">27988363</idno><idno type="doi">10.1016/j.biocel.2016.12.007</idno><idno type="wicri:Area/Main/Corpus">000914</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Corpus" wicri:corpus="PubMed">000914</idno><idno type="wicri:Area/Main/Curation">000914</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Curation">000914</idno><idno type="wicri:Area/Main/Exploration">000914</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">In vitro antiglioma action of indomethacin is mediated via AMP-activated protein kinase/mTOR complex 1 signalling pathway.</title><author><name sortKey="Pantovic, Aleksandar" sort="Pantovic, Aleksandar" uniqKey="Pantovic A" first="Aleksandar" last="Pantovic">Aleksandar Pantovic</name><affiliation wicri:level="1"><nlm:affiliation>Neurology Clinic, Military Medical Academy, Belgrade, Serbia.</nlm:affiliation><country xml:lang="fr">Serbie</country><wicri:regionArea>Neurology Clinic, Military Medical Academy, Belgrade</wicri:regionArea><wicri:noRegion>Belgrade</wicri:noRegion></affiliation></author><author><name sortKey="Bosnjak, Mihajlo" sort="Bosnjak, Mihajlo" uniqKey="Bosnjak M" first="Mihajlo" last="Bosnjak">Mihajlo Bosnjak</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Histology and Embryology, School of Medicine, University of Belgrade, Belgrade, Serbia.</nlm:affiliation><country xml:lang="fr">Serbie</country><wicri:regionArea>Institute of Histology and Embryology, School of Medicine, University of Belgrade, Belgrade</wicri:regionArea><wicri:noRegion>Belgrade</wicri:noRegion></affiliation></author><author><name sortKey="Arsikin, Katarina" sort="Arsikin, Katarina" uniqKey="Arsikin K" first="Katarina" last="Arsikin">Katarina Arsikin</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Dr. Subotica 1, 11000 Belgrade, Serbia.</nlm:affiliation><country xml:lang="fr">Serbie</country><wicri:regionArea>Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Dr. Subotica 1, 11000 Belgrade</wicri:regionArea><wicri:noRegion>11000 Belgrade</wicri:noRegion></affiliation></author><author><name sortKey="Kosic, Milica" sort="Kosic, Milica" uniqKey="Kosic M" first="Milica" last="Kosic">Milica Kosic</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Dr. Subotica 1, 11000 Belgrade, Serbia.</nlm:affiliation><country xml:lang="fr">Serbie</country><wicri:regionArea>Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Dr. Subotica 1, 11000 Belgrade</wicri:regionArea><wicri:noRegion>11000 Belgrade</wicri:noRegion></affiliation></author><author><name sortKey="Mandic, Milos" sort="Mandic, Milos" uniqKey="Mandic M" first="Milos" last="Mandic">Milos Mandic</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Dr. Subotica 1, 11000 Belgrade, Serbia.</nlm:affiliation><country xml:lang="fr">Serbie</country><wicri:regionArea>Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Dr. Subotica 1, 11000 Belgrade</wicri:regionArea><wicri:noRegion>11000 Belgrade</wicri:noRegion></affiliation></author><author><name sortKey="Ristic, Biljana" sort="Ristic, Biljana" uniqKey="Ristic B" first="Biljana" last="Ristic">Biljana Ristic</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Dr. Subotica 1, 11000 Belgrade, Serbia.</nlm:affiliation><country xml:lang="fr">Serbie</country><wicri:regionArea>Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Dr. Subotica 1, 11000 Belgrade</wicri:regionArea><wicri:noRegion>11000 Belgrade</wicri:noRegion></affiliation></author><author><name sortKey="Tosic, Jelena" sort="Tosic, Jelena" uniqKey="Tosic J" first="Jelena" last="Tosic">Jelena Tosic</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Medical and Clinical Biochemistry, School of Medicine, University of Belgrade, Belgrade, Serbia.</nlm:affiliation><country xml:lang="fr">Serbie</country><wicri:regionArea>Institute of Medical and Clinical Biochemistry, School of Medicine, University of Belgrade, Belgrade</wicri:regionArea><wicri:noRegion>Belgrade</wicri:noRegion></affiliation></author><author><name sortKey="Grujicic, Danica" sort="Grujicic, Danica" uniqKey="Grujicic D" first="Danica" last="Grujicic">Danica Grujicic</name><affiliation wicri:level="1"><nlm:affiliation>Clinic of Neurosurgery, Department of Neurooncology, Clinical Centre of Serbia, Belgrade, Serbia.</nlm:affiliation><country xml:lang="fr">Serbie</country><wicri:regionArea>Clinic of Neurosurgery, Department of Neurooncology, Clinical Centre of Serbia, Belgrade</wicri:regionArea><wicri:noRegion>Belgrade</wicri:noRegion></affiliation></author><author><name sortKey="Isakovic, Aleksandra" sort="Isakovic, Aleksandra" uniqKey="Isakovic A" first="Aleksandra" last="Isakovic">Aleksandra Isakovic</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Medical and Clinical Biochemistry, School of Medicine, University of Belgrade, Belgrade, Serbia.</nlm:affiliation><country xml:lang="fr">Serbie</country><wicri:regionArea>Institute of Medical and Clinical Biochemistry, School of Medicine, University of Belgrade, Belgrade</wicri:regionArea><wicri:noRegion>Belgrade</wicri:noRegion></affiliation></author><author><name sortKey="Micic, Nikola" sort="Micic, Nikola" uniqKey="Micic N" first="Nikola" last="Micic">Nikola Micic</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Medical and Clinical Biochemistry, School of Medicine, University of Belgrade, Belgrade, Serbia.</nlm:affiliation><country xml:lang="fr">Serbie</country><wicri:regionArea>Institute of Medical and Clinical Biochemistry, School of Medicine, University of Belgrade, Belgrade</wicri:regionArea><wicri:noRegion>Belgrade</wicri:noRegion></affiliation></author><author><name sortKey="Trajkovic, Vladimir" sort="Trajkovic, Vladimir" uniqKey="Trajkovic V" first="Vladimir" last="Trajkovic">Vladimir Trajkovic</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Dr. Subotica 1, 11000 Belgrade, Serbia. Electronic address: vtrajkovic@med.bg.ac.rs.</nlm:affiliation><country xml:lang="fr">Serbie</country><wicri:regionArea>Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Dr. Subotica 1, 11000 Belgrade</wicri:regionArea><wicri:noRegion>11000 Belgrade</wicri:noRegion></affiliation></author><author><name sortKey="Harhaji Trajkovic, Ljubica" sort="Harhaji Trajkovic, Ljubica" uniqKey="Harhaji Trajkovic L" first="Ljubica" last="Harhaji-Trajkovic">Ljubica Harhaji-Trajkovic</name><affiliation wicri:level="1"><nlm:affiliation>Institute for Biological Research "Sinisa Stankovic", University of Belgrade, Despot Stefan Blvd. 142, 11000 Belgrade, Serbia. Electronic address: buajk@yahoo.com.</nlm:affiliation><country xml:lang="fr">Serbie</country><wicri:regionArea>Institute for Biological Research "Sinisa Stankovic", University of Belgrade, Despot Stefan Blvd. 142, 11000 Belgrade</wicri:regionArea><wicri:noRegion>11000 Belgrade</wicri:noRegion></affiliation></author></analytic><series><title level="j">The international journal of biochemistry & cell biology</title><idno type="eISSN">1878-5875</idno><imprint><date when="2017" type="published">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>AMP-Activated Protein Kinases (antagonists & inhibitors)</term><term>AMP-Activated Protein Kinases (genetics)</term><term>AMP-Activated Protein Kinases (metabolism)</term><term>Adenosine Monophosphate (metabolism)</term><term>Adenosine Triphosphate (metabolism)</term><term>Apoptosis (drug effects)</term><term>Calcium (metabolism)</term><term>Cell Cycle Checkpoints (drug effects)</term><term>Cell Line, Tumor (MeSH)</term><term>Cell Survival (drug effects)</term><term>Cyclooxygenase Inhibitors (pharmacology)</term><term>Glioblastoma (drug therapy)</term><term>Glioblastoma (metabolism)</term><term>Glioma (drug therapy)</term><term>Glioma (metabolism)</term><term>Glioma (pathology)</term><term>Humans (MeSH)</term><term>Indomethacin (pharmacology)</term><term>Mechanistic Target of Rapamycin Complex 1 (MeSH)</term><term>Models, Biological (MeSH)</term><term>Multiprotein Complexes (antagonists & inhibitors)</term><term>Multiprotein Complexes (metabolism)</term><term>RNA, Small Interfering (genetics)</term><term>Signal Transduction (drug effects)</term><term>TOR Serine-Threonine Kinases (antagonists & inhibitors)</term><term>TOR Serine-Threonine Kinases (metabolism)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>AMP (métabolisme)</term><term>AMP-Activated Protein Kinases (antagonistes et inhibiteurs)</term><term>AMP-Activated Protein Kinases (génétique)</term><term>AMP-Activated Protein Kinases (métabolisme)</term><term>Adénosine triphosphate (métabolisme)</term><term>Apoptose (effets des médicaments et des substances chimiques)</term><term>Calcium (métabolisme)</term><term>Complexe-1 cible mécanistique de la rapamycine (MeSH)</term><term>Complexes multiprotéiques (antagonistes et inhibiteurs)</term><term>Complexes multiprotéiques (métabolisme)</term><term>Glioblastome (métabolisme)</term><term>Glioblastome (traitement médicamenteux)</term><term>Gliome (anatomopathologie)</term><term>Gliome (métabolisme)</term><term>Gliome (traitement médicamenteux)</term><term>Humains (MeSH)</term><term>Indométacine (pharmacologie)</term><term>Inhibiteurs des cyclooxygénases (pharmacologie)</term><term>Lignée cellulaire tumorale (MeSH)</term><term>Modèles biologiques (MeSH)</term><term>Petit ARN interférent (génétique)</term><term>Points de contrôle du cycle cellulaire (effets des médicaments et des substances chimiques)</term><term>Survie cellulaire (effets des médicaments et des substances chimiques)</term><term>Sérine-thréonine kinases TOR (antagonistes et inhibiteurs)</term><term>Sérine-thréonine kinases TOR (métabolisme)</term><term>Transduction du signal (effets des médicaments et des substances chimiques)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>AMP-Activated Protein Kinases</term><term>Multiprotein Complexes</term><term>TOR Serine-Threonine Kinases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>AMP-Activated Protein Kinases</term><term>RNA, Small Interfering</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>AMP-Activated Protein Kinases</term><term>Adenosine Monophosphate</term><term>Adenosine Triphosphate</term><term>Calcium</term><term>Multiprotein Complexes</term><term>TOR Serine-Threonine Kinases</term></keywords><keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Gliome</term></keywords><keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>AMP-Activated Protein Kinases</term><term>Complexes multiprotéiques</term><term>Sérine-thréonine kinases TOR</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Apoptosis</term><term>Cell Cycle Checkpoints</term><term>Cell Survival</term><term>Signal Transduction</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Glioblastoma</term><term>Glioma</term></keywords><keywords scheme="MESH" qualifier="effets des médicaments et des substances chimiques" xml:lang="fr"><term>Apoptose</term><term>Points de contrôle du cycle cellulaire</term><term>Survie cellulaire</term><term>Transduction du signal</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>AMP-Activated Protein Kinases</term><term>Petit ARN interférent</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Glioblastoma</term><term>Glioma</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>AMP</term><term>AMP-Activated Protein Kinases</term><term>Adénosine triphosphate</term><term>Calcium</term><term>Complexes multiprotéiques</term><term>Glioblastome</term><term>Gliome</term><term>Sérine-thréonine kinases TOR</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Glioma</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Indométacine</term><term>Inhibiteurs des cyclooxygénases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Cyclooxygenase Inhibitors</term><term>Indomethacin</term></keywords><keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Glioblastome</term><term>Gliome</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Cell Line, Tumor</term><term>Humans</term><term>Mechanistic Target of Rapamycin Complex 1</term><term>Models, Biological</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Complexe-1 cible mécanistique de la rapamycine</term><term>Humains</term><term>Lignée cellulaire tumorale</term><term>Modèles biologiques</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">We investigated the role of the intracellular energy-sensing AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway in the in vitro antiglioma effect of the cyclooxygenase (COX) inhibitor indomethacin. Indomethacin was more potent than COX inhibitors diclofenac, naproxen, and ketoprofen in reducing the viability of U251 human glioma cells. Antiglioma effect of the drug was associated with p21 increase and G<sub>2</sub>M cell cycle arrest, as well as with oxidative stress, mitochondrial depolarization, caspase activation, and the induction of apoptosis. Indomethacin increased the phosphorylation of AMPK and its targets Raptor and acetyl-CoA carboxylase (ACC), and reduced the phosphorylation of mTOR and mTOR complex 1 (mTORC1) substrates p70S6 kinase and PRAS40 (Ser183). AMPK knockdown by RNA interference, as well as the treatment with the mTORC1 activator leucine, prevented indomethacin-mediated mTORC1 inhibition and cytotoxic action, while AMPK activators metformin and AICAR mimicked the effects of the drug. AMPK activation by indomethacin correlated with intracellular ATP depletion and increase in AMP/ATP ratio, and was apparently independent of COX inhibition or the increase in intracellular calcium. Finally, the toxicity of indomethacin towards primary human glioma cells was associated with the activation of AMPK/Raptor/ACC and subsequent suppression of mTORC1/S6K. By demonstrating the involvement of AMPK/mTORC1 pathway in the antiglioma action of indomethacin, our results support its further exploration in glioma therapy.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">27988363</PMID><DateCompleted><Year>2017</Year><Month>11</Month><Day>01</Day></DateCompleted><DateRevised><Year>2017</Year><Month>12</Month><Day>24</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1878-5875</ISSN><JournalIssue CitedMedium="Internet"><Volume>83</Volume><PubDate><Year>2017</Year><Month>02</Month></PubDate></JournalIssue><Title>The international journal of biochemistry & cell biology</Title><ISOAbbreviation>Int J Biochem Cell Biol</ISOAbbreviation></Journal><ArticleTitle>In vitro antiglioma action of indomethacin is mediated via AMP-activated protein kinase/mTOR complex 1 signalling pathway.</ArticleTitle><Pagination><MedlinePgn>84-96</MedlinePgn></Pagination><ELocationID EIdType="pii" ValidYN="Y">S1357-2725(16)30394-6</ELocationID><ELocationID EIdType="doi" ValidYN="Y">10.1016/j.biocel.2016.12.007</ELocationID><Abstract><AbstractText>We investigated the role of the intracellular energy-sensing AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway in the in vitro antiglioma effect of the cyclooxygenase (COX) inhibitor indomethacin. Indomethacin was more potent than COX inhibitors diclofenac, naproxen, and ketoprofen in reducing the viability of U251 human glioma cells. Antiglioma effect of the drug was associated with p21 increase and G<sub>2</sub>M cell cycle arrest, as well as with oxidative stress, mitochondrial depolarization, caspase activation, and the induction of apoptosis. Indomethacin increased the phosphorylation of AMPK and its targets Raptor and acetyl-CoA carboxylase (ACC), and reduced the phosphorylation of mTOR and mTOR complex 1 (mTORC1) substrates p70S6 kinase and PRAS40 (Ser183). AMPK knockdown by RNA interference, as well as the treatment with the mTORC1 activator leucine, prevented indomethacin-mediated mTORC1 inhibition and cytotoxic action, while AMPK activators metformin and AICAR mimicked the effects of the drug. AMPK activation by indomethacin correlated with intracellular ATP depletion and increase in AMP/ATP ratio, and was apparently independent of COX inhibition or the increase in intracellular calcium. Finally, the toxicity of indomethacin towards primary human glioma cells was associated with the activation of AMPK/Raptor/ACC and subsequent suppression of mTORC1/S6K. By demonstrating the involvement of AMPK/mTORC1 pathway in the antiglioma action of indomethacin, our results support its further exploration in glioma therapy.</AbstractText><CopyrightInformation>Copyright © 2016 Elsevier Ltd. All rights reserved.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Pantovic</LastName><ForeName>Aleksandar</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Neurology Clinic, Military Medical Academy, Belgrade, Serbia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bosnjak</LastName><ForeName>Mihajlo</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Institute of Histology and Embryology, School of Medicine, University of Belgrade, Belgrade, Serbia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Arsikin</LastName><ForeName>Katarina</ForeName><Initials>K</Initials><AffiliationInfo><Affiliation>Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Dr. Subotica 1, 11000 Belgrade, Serbia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kosic</LastName><ForeName>Milica</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Dr. Subotica 1, 11000 Belgrade, Serbia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Mandic</LastName><ForeName>Milos</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Dr. Subotica 1, 11000 Belgrade, Serbia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ristic</LastName><ForeName>Biljana</ForeName><Initials>B</Initials><AffiliationInfo><Affiliation>Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Dr. Subotica 1, 11000 Belgrade, Serbia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Tosic</LastName><ForeName>Jelena</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Institute of Medical and Clinical Biochemistry, School of Medicine, University of Belgrade, Belgrade, Serbia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Grujicic</LastName><ForeName>Danica</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>Clinic of Neurosurgery, Department of Neurooncology, Clinical Centre of Serbia, Belgrade, Serbia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Isakovic</LastName><ForeName>Aleksandra</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Institute of Medical and Clinical Biochemistry, School of Medicine, University of Belgrade, Belgrade, Serbia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Micic</LastName><ForeName>Nikola</ForeName><Initials>N</Initials><AffiliationInfo><Affiliation>Institute of Medical and Clinical Biochemistry, School of Medicine, University of Belgrade, Belgrade, Serbia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Trajkovic</LastName><ForeName>Vladimir</ForeName><Initials>V</Initials><AffiliationInfo><Affiliation>Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Dr. Subotica 1, 11000 Belgrade, Serbia. Electronic address: vtrajkovic@med.bg.ac.rs.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Harhaji-Trajkovic</LastName><ForeName>Ljubica</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>Institute for Biological Research "Sinisa Stankovic", University of Belgrade, Despot Stefan Blvd. 142, 11000 Belgrade, Serbia. Electronic address: buajk@yahoo.com.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2016</Year><Month>12</Month><Day>14</Day></ArticleDate></Article><MedlineJournalInfo><Country>Netherlands</Country><MedlineTA>Int J Biochem Cell Biol</MedlineTA><NlmUniqueID>9508482</NlmUniqueID><ISSNLinking>1357-2725</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D016861">Cyclooxygenase Inhibitors</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D046912">Multiprotein Complexes</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D034741">RNA, Small Interfering</NameOfSubstance></Chemical><Chemical><RegistryNumber>415SHH325A</RegistryNumber><NameOfSubstance UI="D000249">Adenosine Monophosphate</NameOfSubstance></Chemical><Chemical><RegistryNumber>8L70Q75FXE</RegistryNumber><NameOfSubstance UI="D000255">Adenosine Triphosphate</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.1.1</RegistryNumber><NameOfSubstance UI="D058570">TOR Serine-Threonine Kinases</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.11.1</RegistryNumber><NameOfSubstance UI="D000076222">Mechanistic Target of Rapamycin Complex 1</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.11.31</RegistryNumber><NameOfSubstance UI="D055372">AMP-Activated Protein Kinases</NameOfSubstance></Chemical><Chemical><RegistryNumber>SY7Q814VUP</RegistryNumber><NameOfSubstance UI="D002118">Calcium</NameOfSubstance></Chemical><Chemical><RegistryNumber>XXE1CET956</RegistryNumber><NameOfSubstance UI="D007213">Indomethacin</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D055372" MajorTopicYN="N">AMP-Activated Protein Kinases</DescriptorName><QualifierName UI="Q000037" MajorTopicYN="N">antagonists & inhibitors</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000249" MajorTopicYN="N">Adenosine Monophosphate</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000255" MajorTopicYN="N">Adenosine Triphosphate</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D017209" MajorTopicYN="N">Apoptosis</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D002118" MajorTopicYN="N">Calcium</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D059447" MajorTopicYN="N">Cell Cycle Checkpoints</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D045744" MajorTopicYN="N">Cell Line, Tumor</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D002470" MajorTopicYN="N">Cell Survival</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D016861" MajorTopicYN="N">Cyclooxygenase Inhibitors</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005909" MajorTopicYN="N">Glioblastoma</DescriptorName><QualifierName UI="Q000188" MajorTopicYN="N">drug therapy</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005910" MajorTopicYN="N">Glioma</DescriptorName><QualifierName UI="Q000188" MajorTopicYN="Y">drug therapy</QualifierName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName><QualifierName UI="Q000473" MajorTopicYN="N">pathology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D007213" MajorTopicYN="N">Indomethacin</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000076222" MajorTopicYN="N">Mechanistic Target of Rapamycin Complex 1</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008954" MajorTopicYN="N">Models, Biological</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D046912" MajorTopicYN="N">Multiprotein Complexes</DescriptorName><QualifierName UI="Q000037" MajorTopicYN="Y">antagonists & inhibitors</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D034741" MajorTopicYN="N">RNA, Small Interfering</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D015398" MajorTopicYN="N">Signal Transduction</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D058570" MajorTopicYN="N">TOR Serine-Threonine Kinases</DescriptorName><QualifierName UI="Q000037" MajorTopicYN="Y">antagonists & inhibitors</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading></MeshHeadingList><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="Y">AMPK</Keyword><Keyword MajorTopicYN="Y">Apoptosis</Keyword><Keyword MajorTopicYN="Y">Glioma</Keyword><Keyword MajorTopicYN="Y">Indomethacin</Keyword><Keyword MajorTopicYN="Y">mTOR</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2016</Year><Month>07</Month><Day>27</Day></PubMedPubDate><PubMedPubDate PubStatus="revised"><Year>2016</Year><Month>10</Month><Day>31</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2016</Year><Month>12</Month><Day>12</Day></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2016</Year><Month>12</Month><Day>19</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2017</Year><Month>11</Month><Day>2</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2016</Year><Month>12</Month><Day>19</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">27988363</ArticleId><ArticleId IdType="pii">S1357-2725(16)30394-6</ArticleId><ArticleId IdType="doi">10.1016/j.biocel.2016.12.007</ArticleId></ArticleIdList></PubmedData></pubmed><affiliations><list><country><li>Serbie</li></country></list><tree><country name="Serbie"><noRegion><name sortKey="Pantovic, Aleksandar" sort="Pantovic, Aleksandar" uniqKey="Pantovic A" first="Aleksandar" last="Pantovic">Aleksandar Pantovic</name></noRegion><name sortKey="Arsikin, Katarina" sort="Arsikin, Katarina" uniqKey="Arsikin K" first="Katarina" last="Arsikin">Katarina Arsikin</name><name sortKey="Bosnjak, Mihajlo" sort="Bosnjak, Mihajlo" uniqKey="Bosnjak M" first="Mihajlo" last="Bosnjak">Mihajlo Bosnjak</name><name sortKey="Grujicic, Danica" sort="Grujicic, Danica" uniqKey="Grujicic D" first="Danica" last="Grujicic">Danica Grujicic</name><name sortKey="Harhaji Trajkovic, Ljubica" sort="Harhaji Trajkovic, Ljubica" uniqKey="Harhaji Trajkovic L" first="Ljubica" last="Harhaji-Trajkovic">Ljubica Harhaji-Trajkovic</name><name sortKey="Isakovic, Aleksandra" sort="Isakovic, Aleksandra" uniqKey="Isakovic A" first="Aleksandra" last="Isakovic">Aleksandra Isakovic</name><name sortKey="Kosic, Milica" sort="Kosic, Milica" uniqKey="Kosic M" first="Milica" last="Kosic">Milica Kosic</name><name sortKey="Mandic, Milos" sort="Mandic, Milos" uniqKey="Mandic M" first="Milos" last="Mandic">Milos Mandic</name><name sortKey="Micic, Nikola" sort="Micic, Nikola" uniqKey="Micic N" first="Nikola" last="Micic">Nikola Micic</name><name sortKey="Ristic, Biljana" sort="Ristic, Biljana" uniqKey="Ristic B" first="Biljana" last="Ristic">Biljana Ristic</name><name sortKey="Tosic, Jelena" sort="Tosic, Jelena" uniqKey="Tosic J" first="Jelena" last="Tosic">Jelena Tosic</name><name sortKey="Trajkovic, Vladimir" sort="Trajkovic, Vladimir" uniqKey="Trajkovic V" first="Vladimir" last="Trajkovic">Vladimir Trajkovic</name></country></tree></affiliations></record>Pour manipuler ce 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