Energy metabolism in H460 lung cancer cells: effects of histone deacetylase inhibitors
Tumor cells are characterized by accelerated growth usually accompanied by up-regulated pathways that ultimately increase the rate of ATP production. These cells can suffer metabolic reprogramming, resulting in distinct bioenergetic phenotypes, generally enhancing glycolysis channeled to lactate pro...
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| Veröffentlicht in: | PloS one 2011-07, Vol.6 (7), p.e22264-e22264 |
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| creator | Amoêdo, Nívea Dias Rodrigues, Mariana Figueiredo Pezzuto, Paula Galina, Antonio da Costa, Rodrigo Madeiro de Almeida, Fábio Ceneviva Lacerda El-Bacha, Tatiana Rumjanek, Franklin David |
| description | Tumor cells are characterized by accelerated growth usually accompanied by up-regulated pathways that ultimately increase the rate of ATP production. These cells can suffer metabolic reprogramming, resulting in distinct bioenergetic phenotypes, generally enhancing glycolysis channeled to lactate production. In the present work we showed metabolic reprogramming by means of inhibitors of histone deacetylase (HDACis), sodium butyrate and trichostatin. This treatment was able to shift energy metabolism by activating mitochondrial systems such as the respiratory chain and oxidative phosphorylation that were largely repressed in the untreated controls.
Various cellular and biochemical parameters were evaluated in lung cancer H460 cells treated with the histone deacetylase inhibitors (HDACis), sodium butyrate (NaB) and trichostatin A (TSA). NaB and TSA reduced glycolytic flux, assayed by lactate release by H460 cells in a concentration dependent manner. NaB inhibited the expression of glucose transporter type 1 (GLUT 1), but substantially increased mitochondria bound hexokinase (HK) activity. NaB induced increase in HK activity was associated to isoform HK I and was accompanied by 1.5 fold increase in HK I mRNA expression and cognate protein biosynthesis. Lactate dehydrogenase (LDH) and pyruvate kinase (PYK) activities were unchanged by HDACis suggesting that the increase in the HK activity was not coupled to glycolytic flux. High resolution respirometry of H460 cells revealed NaB-dependent increased rates of oxygen consumption coupled to ATP synthesis. Metabolomic analysis showed that NaB altered the glycolytic metabolite profile of intact H460 cells. Concomitantly we detected an activation of the pentose phosphate pathway (PPP). The high O(2) consumption in NaB-treated cells was shown to be unrelated to mitochondrial biogenesis since citrate synthase (CS) activity and the amount of mitochondrial DNA remained unchanged.
NaB and TSA induced an increase in mitochondrial function and oxidative metabolism in H460 lung tumor cells concomitant with a less proliferative cellular phenotype. |
| doi_str_mv | 10.1371/journal.pone.0022264 |
| format | Article |
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Various cellular and biochemical parameters were evaluated in lung cancer H460 cells treated with the histone deacetylase inhibitors (HDACis), sodium butyrate (NaB) and trichostatin A (TSA). NaB and TSA reduced glycolytic flux, assayed by lactate release by H460 cells in a concentration dependent manner. NaB inhibited the expression of glucose transporter type 1 (GLUT 1), but substantially increased mitochondria bound hexokinase (HK) activity. NaB induced increase in HK activity was associated to isoform HK I and was accompanied by 1.5 fold increase in HK I mRNA expression and cognate protein biosynthesis. Lactate dehydrogenase (LDH) and pyruvate kinase (PYK) activities were unchanged by HDACis suggesting that the increase in the HK activity was not coupled to glycolytic flux. High resolution respirometry of H460 cells revealed NaB-dependent increased rates of oxygen consumption coupled to ATP synthesis. Metabolomic analysis showed that NaB altered the glycolytic metabolite profile of intact H460 cells. Concomitantly we detected an activation of the pentose phosphate pathway (PPP). The high O(2) consumption in NaB-treated cells was shown to be unrelated to mitochondrial biogenesis since citrate synthase (CS) activity and the amount of mitochondrial DNA remained unchanged.
NaB and TSA induced an increase in mitochondrial function and oxidative metabolism in H460 lung tumor cells concomitant with a less proliferative cellular phenotype.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0022264</identifier><identifier>PMID: 21789245</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Apoptosis ; ATP ; Bioenergetics ; Biology ; Biosynthesis ; Butyrates - pharmacology ; Cancer ; Cell cycle ; Cell Cycle - drug effects ; Cell Differentiation - drug effects ; Cell Line, Tumor ; Cell Membrane Permeability - drug effects ; Cell Proliferation - drug effects ; Cell Respiration - drug effects ; Cell Shape - drug effects ; Chromatin ; Cytochrome ; Dehydrogenases ; Deoxyribonucleic acid ; DNA ; Electron transport ; Energy metabolism ; Energy Metabolism - drug effects ; Enzymes ; Esters ; Fatty acids ; Gene expression ; Glucose 1-Dehydrogenase - metabolism ; Glucose metabolism ; Glucose transporter ; Glucose Transporter Type 1 - metabolism ; Glucose Transporter Type 3 - metabolism ; Glycolysis ; Glycolysis - drug effects ; Hexokinase ; Hexokinase - metabolism ; Histone deacetylase ; Histone Deacetylase Inhibitors - pharmacology ; Humans ; Hydroxamic Acids - pharmacology ; Hypotheses ; Inhibitors ; Kinases ; L-Lactate dehydrogenase ; L-Lactate Dehydrogenase - metabolism ; Lactate dehydrogenase ; Lactates - metabolism ; Lactic acid ; Lung cancer ; Lung diseases ; Lung Neoplasms - enzymology ; Lung Neoplasms - metabolism ; Lung Neoplasms - pathology ; Medicine ; Metabolism ; Metabolites ; Metabolomics ; Mitochondria ; Mitochondria - drug effects ; Mitochondria - metabolism ; Mitochondrial DNA ; Oxidation ; Oxidative metabolism ; Oxidative phosphorylation ; Oxygen ; Oxygen consumption ; Pentose ; Pentose phosphate pathway ; Phosphates ; Phosphorylation ; Physiological aspects ; Protein Binding - drug effects ; Protein biosynthesis ; Protein folding ; Protein synthesis ; Proteins ; Pyruvate kinase ; Pyruvate Kinase - metabolism ; Pyruvic acid ; Respirometry ; RNA ; Rodents ; Sodium ; Sodium butyrate ; Succinate Dehydrogenase - metabolism ; Trends ; Trichostatin A ; Tumor cells</subject><ispartof>PloS one, 2011-07, Vol.6 (7), p.e22264-e22264</ispartof><rights>COPYRIGHT 2011 Public Library of Science</rights><rights>2011 Amoêdo et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Amoêdo et al. 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c757t-e7a43c00045a855a55c7d2e6e78c34782b18eb070d3f442cb9a103c919c0674a3</citedby><cites>FETCH-LOGICAL-c757t-e7a43c00045a855a55c7d2e6e78c34782b18eb070d3f442cb9a103c919c0674a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3138778/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3138778/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21789245$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Amoêdo, Nívea Dias</creatorcontrib><creatorcontrib>Rodrigues, Mariana Figueiredo</creatorcontrib><creatorcontrib>Pezzuto, Paula</creatorcontrib><creatorcontrib>Galina, Antonio</creatorcontrib><creatorcontrib>da Costa, Rodrigo Madeiro</creatorcontrib><creatorcontrib>de Almeida, Fábio Ceneviva Lacerda</creatorcontrib><creatorcontrib>El-Bacha, Tatiana</creatorcontrib><creatorcontrib>Rumjanek, Franklin David</creatorcontrib><title>Energy metabolism in H460 lung cancer cells: effects of histone deacetylase inhibitors</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Tumor cells are characterized by accelerated growth usually accompanied by up-regulated pathways that ultimately increase the rate of ATP production. These cells can suffer metabolic reprogramming, resulting in distinct bioenergetic phenotypes, generally enhancing glycolysis channeled to lactate production. In the present work we showed metabolic reprogramming by means of inhibitors of histone deacetylase (HDACis), sodium butyrate and trichostatin. This treatment was able to shift energy metabolism by activating mitochondrial systems such as the respiratory chain and oxidative phosphorylation that were largely repressed in the untreated controls.
Various cellular and biochemical parameters were evaluated in lung cancer H460 cells treated with the histone deacetylase inhibitors (HDACis), sodium butyrate (NaB) and trichostatin A (TSA). NaB and TSA reduced glycolytic flux, assayed by lactate release by H460 cells in a concentration dependent manner. NaB inhibited the expression of glucose transporter type 1 (GLUT 1), but substantially increased mitochondria bound hexokinase (HK) activity. NaB induced increase in HK activity was associated to isoform HK I and was accompanied by 1.5 fold increase in HK I mRNA expression and cognate protein biosynthesis. Lactate dehydrogenase (LDH) and pyruvate kinase (PYK) activities were unchanged by HDACis suggesting that the increase in the HK activity was not coupled to glycolytic flux. High resolution respirometry of H460 cells revealed NaB-dependent increased rates of oxygen consumption coupled to ATP synthesis. Metabolomic analysis showed that NaB altered the glycolytic metabolite profile of intact H460 cells. Concomitantly we detected an activation of the pentose phosphate pathway (PPP). The high O(2) consumption in NaB-treated cells was shown to be unrelated to mitochondrial biogenesis since citrate synthase (CS) activity and the amount of mitochondrial DNA remained unchanged.
NaB and TSA induced an increase in mitochondrial function and oxidative metabolism in H460 lung tumor cells concomitant with a less proliferative cellular phenotype.</description><subject>Apoptosis</subject><subject>ATP</subject><subject>Bioenergetics</subject><subject>Biology</subject><subject>Biosynthesis</subject><subject>Butyrates - pharmacology</subject><subject>Cancer</subject><subject>Cell cycle</subject><subject>Cell Cycle - drug effects</subject><subject>Cell Differentiation - drug effects</subject><subject>Cell Line, Tumor</subject><subject>Cell Membrane Permeability - drug effects</subject><subject>Cell Proliferation - drug effects</subject><subject>Cell Respiration - drug effects</subject><subject>Cell Shape - drug effects</subject><subject>Chromatin</subject><subject>Cytochrome</subject><subject>Dehydrogenases</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>Electron transport</subject><subject>Energy metabolism</subject><subject>Energy Metabolism - drug effects</subject><subject>Enzymes</subject><subject>Esters</subject><subject>Fatty acids</subject><subject>Gene expression</subject><subject>Glucose 1-Dehydrogenase - metabolism</subject><subject>Glucose metabolism</subject><subject>Glucose transporter</subject><subject>Glucose Transporter Type 1 - metabolism</subject><subject>Glucose Transporter Type 3 - metabolism</subject><subject>Glycolysis</subject><subject>Glycolysis - drug effects</subject><subject>Hexokinase</subject><subject>Hexokinase - metabolism</subject><subject>Histone deacetylase</subject><subject>Histone Deacetylase Inhibitors - pharmacology</subject><subject>Humans</subject><subject>Hydroxamic Acids - pharmacology</subject><subject>Hypotheses</subject><subject>Inhibitors</subject><subject>Kinases</subject><subject>L-Lactate dehydrogenase</subject><subject>L-Lactate Dehydrogenase - metabolism</subject><subject>Lactate dehydrogenase</subject><subject>Lactates - metabolism</subject><subject>Lactic acid</subject><subject>Lung cancer</subject><subject>Lung diseases</subject><subject>Lung Neoplasms - enzymology</subject><subject>Lung Neoplasms - metabolism</subject><subject>Lung Neoplasms - pathology</subject><subject>Medicine</subject><subject>Metabolism</subject><subject>Metabolites</subject><subject>Metabolomics</subject><subject>Mitochondria</subject><subject>Mitochondria - drug effects</subject><subject>Mitochondria - metabolism</subject><subject>Mitochondrial DNA</subject><subject>Oxidation</subject><subject>Oxidative metabolism</subject><subject>Oxidative phosphorylation</subject><subject>Oxygen</subject><subject>Oxygen consumption</subject><subject>Pentose</subject><subject>Pentose phosphate pathway</subject><subject>Phosphates</subject><subject>Phosphorylation</subject><subject>Physiological aspects</subject><subject>Protein Binding - drug effects</subject><subject>Protein biosynthesis</subject><subject>Protein folding</subject><subject>Protein synthesis</subject><subject>Proteins</subject><subject>Pyruvate kinase</subject><subject>Pyruvate Kinase - metabolism</subject><subject>Pyruvic acid</subject><subject>Respirometry</subject><subject>RNA</subject><subject>Rodents</subject><subject>Sodium</subject><subject>Sodium butyrate</subject><subject>Succinate Dehydrogenase - metabolism</subject><subject>Trends</subject><subject>Trichostatin A</subject><subject>Tumor cells</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNkl2L1DAUhoso7rr6D0QLguLFjEmTNKkXwrKs7sDCgh97G9L0tJMhbcYkFeffm3G6y1T2QnKRcPK870nOOVn2EqMlJhx_2LjRD8out26AJUJFUZT0UXaKK1IsygKRx0fnk-xZCBuEGBFl-TQ7KTAXVUHZaXZ7OYDvdnkPUdXOmtDnZsivaIlyOw5drtWgwecarA0fc2hb0DHkrs3XJsSUOW9AaYg7qwIk5drUJjofnmdPWmUDvJj2s-zH58vvF1eL65svq4vz64XmjMcFcEWJRghRpgRjijHNmwJK4EITykVRYwE14qghLaWFriuFEdEVrjQqOVXkLHt98N1aF-RUkiAxQSUmlBU0EasD0Ti1kVtveuV30ikj_wac76Ty0WgLUlHgWhMiiKJU06pqRN0oVjatallVsuT1aco21j00GobolZ2Zzm8Gs5ad-yUJJoJzkQzeTQbe_RwhRNmbsK-tGsCNQQpeUYFJVSTyzT_kw5-bqE6l95uhdSmt3nvKc8pLIWjqeKKWD1BpNdAbnZrYmhSfCd7PBImJ8Dt2agxBrr59_X_25nbOvj1i16BsXAdnx2jcEOYgPYDauxA8tPc1xkjup_-uGnI__XKa_iR7ddyfe9HduJM_--r-Vw</recordid><startdate>20110718</startdate><enddate>20110718</enddate><creator>Amoêdo, Nívea Dias</creator><creator>Rodrigues, Mariana Figueiredo</creator><creator>Pezzuto, Paula</creator><creator>Galina, Antonio</creator><creator>da Costa, Rodrigo Madeiro</creator><creator>de Almeida, Fábio Ceneviva Lacerda</creator><creator>El-Bacha, Tatiana</creator><creator>Rumjanek, Franklin David</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20110718</creationdate><title>Energy metabolism in H460 lung cancer cells: effects of histone deacetylase inhibitors</title><author>Amoêdo, Nívea Dias ; Rodrigues, Mariana Figueiredo ; Pezzuto, Paula ; Galina, Antonio ; da Costa, Rodrigo Madeiro ; de Almeida, Fábio Ceneviva Lacerda ; El-Bacha, Tatiana ; Rumjanek, Franklin David</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c757t-e7a43c00045a855a55c7d2e6e78c34782b18eb070d3f442cb9a103c919c0674a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Apoptosis</topic><topic>ATP</topic><topic>Bioenergetics</topic><topic>Biology</topic><topic>Biosynthesis</topic><topic>Butyrates - 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drug effects</topic><topic>Protein biosynthesis</topic><topic>Protein folding</topic><topic>Protein synthesis</topic><topic>Proteins</topic><topic>Pyruvate kinase</topic><topic>Pyruvate Kinase - metabolism</topic><topic>Pyruvic acid</topic><topic>Respirometry</topic><topic>RNA</topic><topic>Rodents</topic><topic>Sodium</topic><topic>Sodium butyrate</topic><topic>Succinate Dehydrogenase - metabolism</topic><topic>Trends</topic><topic>Trichostatin A</topic><topic>Tumor cells</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Amoêdo, Nívea Dias</creatorcontrib><creatorcontrib>Rodrigues, Mariana Figueiredo</creatorcontrib><creatorcontrib>Pezzuto, Paula</creatorcontrib><creatorcontrib>Galina, Antonio</creatorcontrib><creatorcontrib>da Costa, Rodrigo Madeiro</creatorcontrib><creatorcontrib>de Almeida, Fábio Ceneviva Lacerda</creatorcontrib><creatorcontrib>El-Bacha, Tatiana</creatorcontrib><creatorcontrib>Rumjanek, Franklin David</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Amoêdo, Nívea Dias</au><au>Rodrigues, Mariana Figueiredo</au><au>Pezzuto, Paula</au><au>Galina, Antonio</au><au>da Costa, Rodrigo Madeiro</au><au>de Almeida, Fábio Ceneviva Lacerda</au><au>El-Bacha, Tatiana</au><au>Rumjanek, Franklin David</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Energy metabolism in H460 lung cancer cells: effects of histone deacetylase inhibitors</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2011-07-18</date><risdate>2011</risdate><volume>6</volume><issue>7</issue><spage>e22264</spage><epage>e22264</epage><pages>e22264-e22264</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Tumor cells are characterized by accelerated growth usually accompanied by up-regulated pathways that ultimately increase the rate of ATP production. These cells can suffer metabolic reprogramming, resulting in distinct bioenergetic phenotypes, generally enhancing glycolysis channeled to lactate production. In the present work we showed metabolic reprogramming by means of inhibitors of histone deacetylase (HDACis), sodium butyrate and trichostatin. This treatment was able to shift energy metabolism by activating mitochondrial systems such as the respiratory chain and oxidative phosphorylation that were largely repressed in the untreated controls.
Various cellular and biochemical parameters were evaluated in lung cancer H460 cells treated with the histone deacetylase inhibitors (HDACis), sodium butyrate (NaB) and trichostatin A (TSA). NaB and TSA reduced glycolytic flux, assayed by lactate release by H460 cells in a concentration dependent manner. NaB inhibited the expression of glucose transporter type 1 (GLUT 1), but substantially increased mitochondria bound hexokinase (HK) activity. NaB induced increase in HK activity was associated to isoform HK I and was accompanied by 1.5 fold increase in HK I mRNA expression and cognate protein biosynthesis. Lactate dehydrogenase (LDH) and pyruvate kinase (PYK) activities were unchanged by HDACis suggesting that the increase in the HK activity was not coupled to glycolytic flux. High resolution respirometry of H460 cells revealed NaB-dependent increased rates of oxygen consumption coupled to ATP synthesis. Metabolomic analysis showed that NaB altered the glycolytic metabolite profile of intact H460 cells. Concomitantly we detected an activation of the pentose phosphate pathway (PPP). The high O(2) consumption in NaB-treated cells was shown to be unrelated to mitochondrial biogenesis since citrate synthase (CS) activity and the amount of mitochondrial DNA remained unchanged.
NaB and TSA induced an increase in mitochondrial function and oxidative metabolism in H460 lung tumor cells concomitant with a less proliferative cellular phenotype.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>21789245</pmid><doi>10.1371/journal.pone.0022264</doi><tpages>e22264</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2011-07, Vol.6 (7), p.e22264-e22264 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1306134524 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Apoptosis ATP Bioenergetics Biology Biosynthesis Butyrates - pharmacology Cancer Cell cycle Cell Cycle - drug effects Cell Differentiation - drug effects Cell Line, Tumor Cell Membrane Permeability - drug effects Cell Proliferation - drug effects Cell Respiration - drug effects Cell Shape - drug effects Chromatin Cytochrome Dehydrogenases Deoxyribonucleic acid DNA Electron transport Energy metabolism Energy Metabolism - drug effects Enzymes Esters Fatty acids Gene expression Glucose 1-Dehydrogenase - metabolism Glucose metabolism Glucose transporter Glucose Transporter Type 1 - metabolism Glucose Transporter Type 3 - metabolism Glycolysis Glycolysis - drug effects Hexokinase Hexokinase - metabolism Histone deacetylase Histone Deacetylase Inhibitors - pharmacology Humans Hydroxamic Acids - pharmacology Hypotheses Inhibitors Kinases L-Lactate dehydrogenase L-Lactate Dehydrogenase - metabolism Lactate dehydrogenase Lactates - metabolism Lactic acid Lung cancer Lung diseases Lung Neoplasms - enzymology Lung Neoplasms - metabolism Lung Neoplasms - pathology Medicine Metabolism Metabolites Metabolomics Mitochondria Mitochondria - drug effects Mitochondria - metabolism Mitochondrial DNA Oxidation Oxidative metabolism Oxidative phosphorylation Oxygen Oxygen consumption Pentose Pentose phosphate pathway Phosphates Phosphorylation Physiological aspects Protein Binding - drug effects Protein biosynthesis Protein folding Protein synthesis Proteins Pyruvate kinase Pyruvate Kinase - metabolism Pyruvic acid Respirometry RNA Rodents Sodium Sodium butyrate Succinate Dehydrogenase - metabolism Trends Trichostatin A Tumor cells |
| title | Energy metabolism in H460 lung cancer cells: effects of histone deacetylase inhibitors |
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