PDK-1 regulates lactate production in hypoxia and is associated with poor prognosis in head and neck squamous cancer
Here we describe the expression and function of a HIF-1-regulated protein pyruvate dehydrogenase kinase-1 (PDK-1) in head and neck squamous cancer (HNSCC). Using RNAi to downregulate hypoxia-inducible PDK-1, we found that lactate and pyruvate excretion after 16–48 h of hypoxia was suppressed to norm...
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| Veröffentlicht in: | British journal of cancer 2008-06, Vol.98 (12), p.1975-1984 |
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| container_end_page | 1984 |
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| container_issue | 12 |
| container_start_page | 1975 |
| container_title | British journal of cancer |
| container_volume | 98 |
| creator | Wigfield, S M Winter, S C Giatromanolaki, A Taylor, J Koukourakis, M L Harris, A L |
| description | Here we describe the expression and function of a HIF-1-regulated protein pyruvate dehydrogenase kinase-1 (PDK-1) in head and neck squamous cancer (HNSCC). Using RNAi to downregulate hypoxia-inducible PDK-1, we found that lactate and pyruvate excretion after 16–48 h of hypoxia was suppressed to normoxic levels. This indicates that PDK-1 plays an important role in maintaining glycolysis. Knockdown had no effect on proliferation or survival under hypoxia. The immunohistochemical expression of PDK-1 was assessed in 140 cases of HNSCC. PDK-1 expression was not expressed in normal tissues but was upregulated in HNSCC and found to be predominantly cytoplasmic with occasional strong focal nuclear expression. It was strongly related to poor outcome (
P
=0.005 split by median). These results indicate that HIF regulation of PDK-1 has a key role in maintaining lactate production in human cancer and that the investigation of PDK-1 inhibitors should be investigated for antitumour effects. |
| doi_str_mv | 10.1038/sj.bjc.6604356 |
| format | Article |
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P
=0.005 split by median). These results indicate that HIF regulation of PDK-1 has a key role in maintaining lactate production in human cancer and that the investigation of PDK-1 inhibitors should be investigated for antitumour effects.</description><identifier>ISSN: 0007-0920</identifier><identifier>EISSN: 1532-1827</identifier><identifier>DOI: 10.1038/sj.bjc.6604356</identifier><identifier>PMID: 18542064</identifier><identifier>CODEN: BJCAAI</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>Base Sequence ; Biomedical and Life Sciences ; Biomedicine ; Cancer Research ; Carcinoma, Squamous Cell - metabolism ; Carcinoma, Squamous Cell - pathology ; Cell culture ; Cell Line, Tumor ; Dehydrogenases ; DNA Primers ; Drug Resistance ; Enzymes ; Epidemiology ; Gene Silencing ; Head & neck cancer ; Head and Neck Neoplasms - metabolism ; Head and Neck Neoplasms - pathology ; Humans ; Hypoxia ; Hypoxia - metabolism ; Kinases ; Lactic Acid - biosynthesis ; Medical prognosis ; Medical research ; Molecular Diagnostics ; Molecular Medicine ; Oncology ; Polymerase Chain Reaction ; Prognosis ; Protein Serine-Threonine Kinases - physiology ; Pyruvate Dehydrogenase Acetyl-Transferring Kinase ; RNA Interference ; Transcription factors</subject><ispartof>British journal of cancer, 2008-06, Vol.98 (12), p.1975-1984</ispartof><rights>The Author(s) 2008</rights><rights>Copyright Nature Publishing Group Jun 17, 2008</rights><rights>Copyright © 2008 Cancer Research UK 2008 Cancer Research UK</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c477t-ee3d2fa24be0407eb9d2c05de6c14af45abc6ccdc64a20c2e62bb945beb28d763</citedby><cites>FETCH-LOGICAL-c477t-ee3d2fa24be0407eb9d2c05de6c14af45abc6ccdc64a20c2e62bb945beb28d763</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/PMC2441961/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2441961/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,724,777,781,882,27906,27907,41470,42539,51301,53773,53775</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18542064$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wigfield, S M</creatorcontrib><creatorcontrib>Winter, S C</creatorcontrib><creatorcontrib>Giatromanolaki, A</creatorcontrib><creatorcontrib>Taylor, J</creatorcontrib><creatorcontrib>Koukourakis, M L</creatorcontrib><creatorcontrib>Harris, A L</creatorcontrib><title>PDK-1 regulates lactate production in hypoxia and is associated with poor prognosis in head and neck squamous cancer</title><title>British journal of cancer</title><addtitle>Br J Cancer</addtitle><addtitle>Br J Cancer</addtitle><description>Here we describe the expression and function of a HIF-1-regulated protein pyruvate dehydrogenase kinase-1 (PDK-1) in head and neck squamous cancer (HNSCC). Using RNAi to downregulate hypoxia-inducible PDK-1, we found that lactate and pyruvate excretion after 16–48 h of hypoxia was suppressed to normoxic levels. This indicates that PDK-1 plays an important role in maintaining glycolysis. Knockdown had no effect on proliferation or survival under hypoxia. The immunohistochemical expression of PDK-1 was assessed in 140 cases of HNSCC. PDK-1 expression was not expressed in normal tissues but was upregulated in HNSCC and found to be predominantly cytoplasmic with occasional strong focal nuclear expression. It was strongly related to poor outcome (
P
=0.005 split by median). These results indicate that HIF regulation of PDK-1 has a key role in maintaining lactate production in human cancer and that the investigation of PDK-1 inhibitors should be investigated for antitumour effects.</description><subject>Base Sequence</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cancer Research</subject><subject>Carcinoma, Squamous Cell - metabolism</subject><subject>Carcinoma, Squamous Cell - pathology</subject><subject>Cell culture</subject><subject>Cell Line, Tumor</subject><subject>Dehydrogenases</subject><subject>DNA Primers</subject><subject>Drug Resistance</subject><subject>Enzymes</subject><subject>Epidemiology</subject><subject>Gene Silencing</subject><subject>Head & neck cancer</subject><subject>Head and Neck Neoplasms - metabolism</subject><subject>Head and Neck Neoplasms - pathology</subject><subject>Humans</subject><subject>Hypoxia</subject><subject>Hypoxia - metabolism</subject><subject>Kinases</subject><subject>Lactic Acid - biosynthesis</subject><subject>Medical prognosis</subject><subject>Medical research</subject><subject>Molecular Diagnostics</subject><subject>Molecular Medicine</subject><subject>Oncology</subject><subject>Polymerase Chain Reaction</subject><subject>Prognosis</subject><subject>Protein Serine-Threonine Kinases - physiology</subject><subject>Pyruvate Dehydrogenase Acetyl-Transferring Kinase</subject><subject>RNA Interference</subject><subject>Transcription factors</subject><issn>0007-0920</issn><issn>1532-1827</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp1kUtv1DAUhS0EotPClh3IYsEuU9tx7GSDhFoeFZVgAWvLjzszDhk7tRNo_309zLQFJFa2db5zfK8OQi8oWVJSt6e5X5reLoUgvG7EI7SgTc0q2jL5GC0IIbIiHSNH6Djnvjw70sqn6Ii2DWdE8AWavp5_rihOsJ4HPUHGg7ZTueAxRTfbyceAfcCbmzFee411cNhnrHOO1hfM4V9-2uAxxrRzrEPMRd4ZQLvfdAD7A-erWW_jnLHVwUJ6hp6s9JDh-eE8Qd8_vP929qm6_PLx4uzdZWW5lFMFUDu20owbIJxIMJ1jljQOhKVcr3ijjRXWOiu4ZsQyEMyYjjcGDGudFPUJervPHWezBWchTEkPakx-q9ONitqrv5XgN2odfyrGOe0ELQFvDgEpXs2QJ7X12cIw6ABlHSWpaCXlXQFf_wP2cU6hLKdYTQgVHa8LtNxDNsWcE6zuJ6FE7dpUuVelTXVosxhe_Tn_A36orwCneyAXKawhPXz738iXe0fQ05zgPvJOvwVsHLip</recordid><startdate>20080617</startdate><enddate>20080617</enddate><creator>Wigfield, S M</creator><creator>Winter, S C</creator><creator>Giatromanolaki, A</creator><creator>Taylor, J</creator><creator>Koukourakis, M L</creator><creator>Harris, A L</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</scope><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>3V.</scope><scope>7RV</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AN0</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20080617</creationdate><title>PDK-1 regulates lactate production in hypoxia and is associated with poor prognosis in head and neck squamous cancer</title><author>Wigfield, S M ; Winter, S C ; Giatromanolaki, A ; Taylor, J ; Koukourakis, M L ; Harris, A L</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c477t-ee3d2fa24be0407eb9d2c05de6c14af45abc6ccdc64a20c2e62bb945beb28d763</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Base Sequence</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Cancer Research</topic><topic>Carcinoma, Squamous Cell - metabolism</topic><topic>Carcinoma, Squamous Cell - pathology</topic><topic>Cell culture</topic><topic>Cell Line, Tumor</topic><topic>Dehydrogenases</topic><topic>DNA Primers</topic><topic>Drug Resistance</topic><topic>Enzymes</topic><topic>Epidemiology</topic><topic>Gene Silencing</topic><topic>Head & neck cancer</topic><topic>Head and Neck Neoplasms - metabolism</topic><topic>Head and Neck Neoplasms - pathology</topic><topic>Humans</topic><topic>Hypoxia</topic><topic>Hypoxia - metabolism</topic><topic>Kinases</topic><topic>Lactic Acid - biosynthesis</topic><topic>Medical prognosis</topic><topic>Medical research</topic><topic>Molecular Diagnostics</topic><topic>Molecular Medicine</topic><topic>Oncology</topic><topic>Polymerase Chain Reaction</topic><topic>Prognosis</topic><topic>Protein Serine-Threonine Kinases - physiology</topic><topic>Pyruvate Dehydrogenase Acetyl-Transferring Kinase</topic><topic>RNA Interference</topic><topic>Transcription factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wigfield, S M</creatorcontrib><creatorcontrib>Winter, S C</creatorcontrib><creatorcontrib>Giatromanolaki, A</creatorcontrib><creatorcontrib>Taylor, J</creatorcontrib><creatorcontrib>Koukourakis, M L</creatorcontrib><creatorcontrib>Harris, A L</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Nursing & Allied Health Database</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</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>ProQuest SciTech 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>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>British Nursing Database</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</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>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>British journal of cancer</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wigfield, S M</au><au>Winter, S C</au><au>Giatromanolaki, A</au><au>Taylor, J</au><au>Koukourakis, M L</au><au>Harris, A L</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>PDK-1 regulates lactate production in hypoxia and is associated with poor prognosis in head and neck squamous cancer</atitle><jtitle>British journal of cancer</jtitle><stitle>Br J Cancer</stitle><addtitle>Br J Cancer</addtitle><date>2008-06-17</date><risdate>2008</risdate><volume>98</volume><issue>12</issue><spage>1975</spage><epage>1984</epage><pages>1975-1984</pages><issn>0007-0920</issn><eissn>1532-1827</eissn><coden>BJCAAI</coden><abstract>Here we describe the expression and function of a HIF-1-regulated protein pyruvate dehydrogenase kinase-1 (PDK-1) in head and neck squamous cancer (HNSCC). Using RNAi to downregulate hypoxia-inducible PDK-1, we found that lactate and pyruvate excretion after 16–48 h of hypoxia was suppressed to normoxic levels. This indicates that PDK-1 plays an important role in maintaining glycolysis. Knockdown had no effect on proliferation or survival under hypoxia. The immunohistochemical expression of PDK-1 was assessed in 140 cases of HNSCC. PDK-1 expression was not expressed in normal tissues but was upregulated in HNSCC and found to be predominantly cytoplasmic with occasional strong focal nuclear expression. It was strongly related to poor outcome (
P
=0.005 split by median). These results indicate that HIF regulation of PDK-1 has a key role in maintaining lactate production in human cancer and that the investigation of PDK-1 inhibitors should be investigated for antitumour effects.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>18542064</pmid><doi>10.1038/sj.bjc.6604356</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Base Sequence Biomedical and Life Sciences Biomedicine Cancer Research Carcinoma, Squamous Cell - metabolism Carcinoma, Squamous Cell - pathology Cell culture Cell Line, Tumor Dehydrogenases DNA Primers Drug Resistance Enzymes Epidemiology Gene Silencing Head & neck cancer Head and Neck Neoplasms - metabolism Head and Neck Neoplasms - pathology Humans Hypoxia Hypoxia - metabolism Kinases Lactic Acid - biosynthesis Medical prognosis Medical research Molecular Diagnostics Molecular Medicine Oncology Polymerase Chain Reaction Prognosis Protein Serine-Threonine Kinases - physiology Pyruvate Dehydrogenase Acetyl-Transferring Kinase RNA Interference Transcription factors |
| title | PDK-1 regulates lactate production in hypoxia and is associated with poor prognosis in head and neck squamous cancer |
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