Nrf2-driven TERT regulates pentose phosphate pathway in glioblastoma
Given the involvement of telomerase activation and dysregulated metabolism in glioma progression, the connection between these two critical players was investigated. Pharmacological inhibition of human Telomerase reverse transcriptase (hTERT) by Costunolide induced glioma cell apoptosis in a reactiv...
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| creator | Ahmad, F Dixit, D Sharma, V Kumar, A Joshi, S D Sarkar, C Sen, E |
| description | Given the involvement of telomerase activation and dysregulated metabolism in glioma progression, the connection between these two critical players was investigated. Pharmacological inhibition of human Telomerase reverse transcriptase (hTERT) by Costunolide induced glioma cell apoptosis in a reactive oxygen species (ROS)-dependent manner. Costunolide induced an ROS-dependent increase in p53 abrogated telomerase activity. Costunolide decreased Nrf2 level; and ectopic Nrf2 expression decreased Costunolide-induced ROS generation. While TERT knock-down abrogated Nrf2 levels, overexpression of Nrf2 increased TERT expression. Inhibition of hTERT either by Costunolide, or by siRNA or dominant-negative hTERT (DN-hTERT) abrogated (i) expression of Glucose-6-phosphate dehydrogenase (G6PD) and Transketolase (TKT) – two major nodes in the pentose phosphate (PPP) pathway; and (ii) phosphorylation of glycogen synthase (GS). hTERT knock-down decreased TKT activity and increased glycogen accumulation. Interestingly, siRNA-mediated knock-down of TKT elevated glycogen accumulation. Coherent with the
in vitro
findings, Costunolide reduced tumor burden in heterotypic xenograft glioma mouse model. Costunolide-treated tumors exhibited diminished TKT activity, heightened glycogen accumulation, and increased senescence. Importantly, glioblastoma multiforme (GBM) patient tumors bearing TERT promoter mutations (C228T and C250T) known to be associated with increased telomerase activity; exhibited elevated Nrf2 and TKT expression and decreased glycogen accumulation. Taken together, our findings highlight the previously unknown (i) role of telomerase in the regulation of PPP and glycogen accumulation and (ii) the involvement of Nrf2-TERT loop in maintaining oxidative defense responses in glioma cells. |
| doi_str_mv | 10.1038/cddis.2016.117 |
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| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4917655</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1787471431</sourcerecordid><originalsourceid>FETCH-LOGICAL-c524t-9180b091f37723f9b66eaa073de90adc9e0defc96d1399d9eec21b14283702813</originalsourceid><addsrcrecordid>eNptkUtLAzEUhYMoWtStSxlw42ZqHtM8NoLUJxQFqeuQmdxpp0wnYzJT8d-bWpUqZpOQ--Xcc3MQOiF4SDCTF4W1VRhSTPiQELGDBhRnJM2kVLtb5wN0HMICx8UYpiO-jw6oIJnkkg_Q9aMvaWp9tYImmd48TxMPs742HYSkhaZzAZJ27kI7j1dJa7r5m3lPqiaZ1ZXLaxM6tzRHaK80dYDjr_0QvdzeTMf36eTp7mF8NUmLEc26VBGJc6xIyYSgrFQ552AMFsyCwsYWCrCFslDcEqaUVQAFJTnJqGQCU0nYIbrc6LZ9vgRbRH_e1Lr11dL4d-1MpX9XmmquZ26lM0UEH42iwPmXgHevPYROL6tQQF2bBlwfNBFSZPFv2LrX2R904XrfxPHWFBcqGlKRGm6owrsQPJQ_ZgjW64z0Z0Z6nZGOGcUHp9sj_ODfiUTgYgOEWGpm4Lf6_i_5AR3knTU</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1786792819</pqid></control><display><type>article</type><title>Nrf2-driven TERT regulates pentose phosphate pathway in glioblastoma</title><source>MEDLINE</source><source>Nature Free</source><source>DOAJ Directory of Open Access Journals</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>PubMed Central</source><source>Springer Nature OA Free Journals</source><creator>Ahmad, F ; Dixit, D ; Sharma, V ; Kumar, A ; Joshi, S D ; Sarkar, C ; Sen, E</creator><creatorcontrib>Ahmad, F ; Dixit, D ; Sharma, V ; Kumar, A ; Joshi, S D ; Sarkar, C ; Sen, E</creatorcontrib><description>Given the involvement of telomerase activation and dysregulated metabolism in glioma progression, the connection between these two critical players was investigated. Pharmacological inhibition of human Telomerase reverse transcriptase (hTERT) by Costunolide induced glioma cell apoptosis in a reactive oxygen species (ROS)-dependent manner. Costunolide induced an ROS-dependent increase in p53 abrogated telomerase activity. Costunolide decreased Nrf2 level; and ectopic Nrf2 expression decreased Costunolide-induced ROS generation. While TERT knock-down abrogated Nrf2 levels, overexpression of Nrf2 increased TERT expression. Inhibition of hTERT either by Costunolide, or by siRNA or dominant-negative hTERT (DN-hTERT) abrogated (i) expression of Glucose-6-phosphate dehydrogenase (G6PD) and Transketolase (TKT) – two major nodes in the pentose phosphate (PPP) pathway; and (ii) phosphorylation of glycogen synthase (GS). hTERT knock-down decreased TKT activity and increased glycogen accumulation. Interestingly, siRNA-mediated knock-down of TKT elevated glycogen accumulation. Coherent with the
in vitro
findings, Costunolide reduced tumor burden in heterotypic xenograft glioma mouse model. Costunolide-treated tumors exhibited diminished TKT activity, heightened glycogen accumulation, and increased senescence. Importantly, glioblastoma multiforme (GBM) patient tumors bearing TERT promoter mutations (C228T and C250T) known to be associated with increased telomerase activity; exhibited elevated Nrf2 and TKT expression and decreased glycogen accumulation. Taken together, our findings highlight the previously unknown (i) role of telomerase in the regulation of PPP and glycogen accumulation and (ii) the involvement of Nrf2-TERT loop in maintaining oxidative defense responses in glioma cells.</description><identifier>ISSN: 2041-4889</identifier><identifier>EISSN: 2041-4889</identifier><identifier>DOI: 10.1038/cddis.2016.117</identifier><identifier>PMID: 27148686</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13 ; 13/109 ; 13/2 ; 38 ; 38/77 ; 631/45/612/1245 ; 631/67/1922 ; 631/67/2327 ; 631/80/86 ; 64 ; 64/60 ; 82 ; 82/29 ; Animals ; Antibodies ; Antineoplastic Agents, Phytogenic - pharmacology ; Biochemistry ; Biomedical and Life Sciences ; Brain Neoplasms - drug therapy ; Brain Neoplasms - genetics ; Brain Neoplasms - metabolism ; Brain Neoplasms - pathology ; Cell Biology ; Cell Culture ; Cell Line, Tumor ; Cellular Senescence - drug effects ; Gene Expression Regulation, Neoplastic ; Glioblastoma - drug therapy ; Glioblastoma - genetics ; Glioblastoma - metabolism ; Glioblastoma - pathology ; Glucosephosphate Dehydrogenase - genetics ; Glucosephosphate Dehydrogenase - metabolism ; Glycogen - biosynthesis ; Glycogen Synthase - genetics ; Glycogen Synthase - metabolism ; Humans ; Immunology ; Life Sciences ; Metabolism ; Mice ; Mice, Nude ; NF-E2-Related Factor 2 - antagonists & inhibitors ; NF-E2-Related Factor 2 - genetics ; NF-E2-Related Factor 2 - metabolism ; Original ; original-article ; Pentose Phosphate Pathway - drug effects ; Pentose Phosphate Pathway - genetics ; Phosphates ; Phosphorylation - drug effects ; Reactive Oxygen Species - agonists ; Reactive Oxygen Species - metabolism ; RNA, Small Interfering - genetics ; RNA, Small Interfering - metabolism ; Sesquiterpenes - pharmacology ; Signal Transduction ; Telomerase ; Telomerase - genetics ; Telomerase - metabolism ; Transketolase - antagonists & inhibitors ; Transketolase - genetics ; Transketolase - metabolism ; Tumor Suppressor Protein p53 - genetics ; Tumor Suppressor Protein p53 - metabolism ; Xenograft Model Antitumor Assays</subject><ispartof>Cell death & disease, 2016-05, Vol.7 (5), p.e2213-e2213</ispartof><rights>The Author(s) 2016</rights><rights>Copyright Nature Publishing Group May 2016</rights><rights>Copyright © 2016 Macmillan Publishers Limited 2016 Macmillan Publishers Limited</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c524t-9180b091f37723f9b66eaa073de90adc9e0defc96d1399d9eec21b14283702813</citedby><cites>FETCH-LOGICAL-c524t-9180b091f37723f9b66eaa073de90adc9e0defc96d1399d9eec21b14283702813</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/PMC4917655/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4917655/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27901,27902,41096,42165,51551,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27148686$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ahmad, F</creatorcontrib><creatorcontrib>Dixit, D</creatorcontrib><creatorcontrib>Sharma, V</creatorcontrib><creatorcontrib>Kumar, A</creatorcontrib><creatorcontrib>Joshi, S D</creatorcontrib><creatorcontrib>Sarkar, C</creatorcontrib><creatorcontrib>Sen, E</creatorcontrib><title>Nrf2-driven TERT regulates pentose phosphate pathway in glioblastoma</title><title>Cell death & disease</title><addtitle>Cell Death Dis</addtitle><addtitle>Cell Death Dis</addtitle><description>Given the involvement of telomerase activation and dysregulated metabolism in glioma progression, the connection between these two critical players was investigated. Pharmacological inhibition of human Telomerase reverse transcriptase (hTERT) by Costunolide induced glioma cell apoptosis in a reactive oxygen species (ROS)-dependent manner. Costunolide induced an ROS-dependent increase in p53 abrogated telomerase activity. Costunolide decreased Nrf2 level; and ectopic Nrf2 expression decreased Costunolide-induced ROS generation. While TERT knock-down abrogated Nrf2 levels, overexpression of Nrf2 increased TERT expression. Inhibition of hTERT either by Costunolide, or by siRNA or dominant-negative hTERT (DN-hTERT) abrogated (i) expression of Glucose-6-phosphate dehydrogenase (G6PD) and Transketolase (TKT) – two major nodes in the pentose phosphate (PPP) pathway; and (ii) phosphorylation of glycogen synthase (GS). hTERT knock-down decreased TKT activity and increased glycogen accumulation. Interestingly, siRNA-mediated knock-down of TKT elevated glycogen accumulation. Coherent with the
in vitro
findings, Costunolide reduced tumor burden in heterotypic xenograft glioma mouse model. Costunolide-treated tumors exhibited diminished TKT activity, heightened glycogen accumulation, and increased senescence. Importantly, glioblastoma multiforme (GBM) patient tumors bearing TERT promoter mutations (C228T and C250T) known to be associated with increased telomerase activity; exhibited elevated Nrf2 and TKT expression and decreased glycogen accumulation. Taken together, our findings highlight the previously unknown (i) role of telomerase in the regulation of PPP and glycogen accumulation and (ii) the involvement of Nrf2-TERT loop in maintaining oxidative defense responses in glioma cells.</description><subject>13</subject><subject>13/109</subject><subject>13/2</subject><subject>38</subject><subject>38/77</subject><subject>631/45/612/1245</subject><subject>631/67/1922</subject><subject>631/67/2327</subject><subject>631/80/86</subject><subject>64</subject><subject>64/60</subject><subject>82</subject><subject>82/29</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Antineoplastic Agents, Phytogenic - pharmacology</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Brain Neoplasms - drug therapy</subject><subject>Brain Neoplasms - genetics</subject><subject>Brain Neoplasms - metabolism</subject><subject>Brain Neoplasms - pathology</subject><subject>Cell Biology</subject><subject>Cell Culture</subject><subject>Cell Line, Tumor</subject><subject>Cellular Senescence - 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genetics</subject><subject>Phosphates</subject><subject>Phosphorylation - drug effects</subject><subject>Reactive Oxygen Species - agonists</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>RNA, Small Interfering - genetics</subject><subject>RNA, Small Interfering - metabolism</subject><subject>Sesquiterpenes - pharmacology</subject><subject>Signal Transduction</subject><subject>Telomerase</subject><subject>Telomerase - genetics</subject><subject>Telomerase - metabolism</subject><subject>Transketolase - antagonists & inhibitors</subject><subject>Transketolase - genetics</subject><subject>Transketolase - metabolism</subject><subject>Tumor Suppressor Protein p53 - genetics</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><subject>Xenograft Model Antitumor Assays</subject><issn>2041-4889</issn><issn>2041-4889</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNptkUtLAzEUhYMoWtStSxlw42ZqHtM8NoLUJxQFqeuQmdxpp0wnYzJT8d-bWpUqZpOQ--Xcc3MQOiF4SDCTF4W1VRhSTPiQELGDBhRnJM2kVLtb5wN0HMICx8UYpiO-jw6oIJnkkg_Q9aMvaWp9tYImmd48TxMPs742HYSkhaZzAZJ27kI7j1dJa7r5m3lPqiaZ1ZXLaxM6tzRHaK80dYDjr_0QvdzeTMf36eTp7mF8NUmLEc26VBGJc6xIyYSgrFQ552AMFsyCwsYWCrCFslDcEqaUVQAFJTnJqGQCU0nYIbrc6LZ9vgRbRH_e1Lr11dL4d-1MpX9XmmquZ26lM0UEH42iwPmXgHevPYROL6tQQF2bBlwfNBFSZPFv2LrX2R904XrfxPHWFBcqGlKRGm6owrsQPJQ_ZgjW64z0Z0Z6nZGOGcUHp9sj_ODfiUTgYgOEWGpm4Lf6_i_5AR3knTU</recordid><startdate>20160505</startdate><enddate>20160505</enddate><creator>Ahmad, F</creator><creator>Dixit, D</creator><creator>Sharma, V</creator><creator>Kumar, A</creator><creator>Joshi, S D</creator><creator>Sarkar, C</creator><creator>Sen, E</creator><general>Nature Publishing Group UK</general><general>Springer Nature B.V</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>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88I</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</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>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M2P</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20160505</creationdate><title>Nrf2-driven TERT regulates pentose phosphate pathway in glioblastoma</title><author>Ahmad, F ; Dixit, D ; Sharma, V ; Kumar, A ; Joshi, S D ; Sarkar, C ; Sen, E</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c524t-9180b091f37723f9b66eaa073de90adc9e0defc96d1399d9eec21b14283702813</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>13</topic><topic>13/109</topic><topic>13/2</topic><topic>38</topic><topic>38/77</topic><topic>631/45/612/1245</topic><topic>631/67/1922</topic><topic>631/67/2327</topic><topic>631/80/86</topic><topic>64</topic><topic>64/60</topic><topic>82</topic><topic>82/29</topic><topic>Animals</topic><topic>Antibodies</topic><topic>Antineoplastic Agents, Phytogenic - pharmacology</topic><topic>Biochemistry</topic><topic>Biomedical and Life Sciences</topic><topic>Brain Neoplasms - drug therapy</topic><topic>Brain Neoplasms - genetics</topic><topic>Brain Neoplasms - metabolism</topic><topic>Brain Neoplasms - pathology</topic><topic>Cell Biology</topic><topic>Cell Culture</topic><topic>Cell Line, Tumor</topic><topic>Cellular Senescence - drug effects</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Glioblastoma - drug therapy</topic><topic>Glioblastoma - genetics</topic><topic>Glioblastoma - metabolism</topic><topic>Glioblastoma - pathology</topic><topic>Glucosephosphate Dehydrogenase - genetics</topic><topic>Glucosephosphate Dehydrogenase - metabolism</topic><topic>Glycogen - biosynthesis</topic><topic>Glycogen Synthase - genetics</topic><topic>Glycogen Synthase - metabolism</topic><topic>Humans</topic><topic>Immunology</topic><topic>Life Sciences</topic><topic>Metabolism</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>NF-E2-Related Factor 2 - antagonists & inhibitors</topic><topic>NF-E2-Related Factor 2 - genetics</topic><topic>NF-E2-Related Factor 2 - metabolism</topic><topic>Original</topic><topic>original-article</topic><topic>Pentose Phosphate Pathway - drug effects</topic><topic>Pentose Phosphate Pathway - genetics</topic><topic>Phosphates</topic><topic>Phosphorylation - drug effects</topic><topic>Reactive Oxygen Species - agonists</topic><topic>Reactive Oxygen Species - metabolism</topic><topic>RNA, Small Interfering - genetics</topic><topic>RNA, Small Interfering - metabolism</topic><topic>Sesquiterpenes - pharmacology</topic><topic>Signal Transduction</topic><topic>Telomerase</topic><topic>Telomerase - genetics</topic><topic>Telomerase - metabolism</topic><topic>Transketolase - antagonists & inhibitors</topic><topic>Transketolase - genetics</topic><topic>Transketolase - metabolism</topic><topic>Tumor Suppressor Protein p53 - genetics</topic><topic>Tumor Suppressor Protein p53 - metabolism</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ahmad, F</creatorcontrib><creatorcontrib>Dixit, D</creatorcontrib><creatorcontrib>Sharma, V</creatorcontrib><creatorcontrib>Kumar, A</creatorcontrib><creatorcontrib>Joshi, S D</creatorcontrib><creatorcontrib>Sarkar, C</creatorcontrib><creatorcontrib>Sen, E</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>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</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>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>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>Publicly Available Content Database</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>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cell death & disease</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ahmad, F</au><au>Dixit, D</au><au>Sharma, V</au><au>Kumar, A</au><au>Joshi, S D</au><au>Sarkar, C</au><au>Sen, E</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Nrf2-driven TERT regulates pentose phosphate pathway in glioblastoma</atitle><jtitle>Cell death & disease</jtitle><stitle>Cell Death Dis</stitle><addtitle>Cell Death Dis</addtitle><date>2016-05-05</date><risdate>2016</risdate><volume>7</volume><issue>5</issue><spage>e2213</spage><epage>e2213</epage><pages>e2213-e2213</pages><issn>2041-4889</issn><eissn>2041-4889</eissn><abstract>Given the involvement of telomerase activation and dysregulated metabolism in glioma progression, the connection between these two critical players was investigated. Pharmacological inhibition of human Telomerase reverse transcriptase (hTERT) by Costunolide induced glioma cell apoptosis in a reactive oxygen species (ROS)-dependent manner. Costunolide induced an ROS-dependent increase in p53 abrogated telomerase activity. Costunolide decreased Nrf2 level; and ectopic Nrf2 expression decreased Costunolide-induced ROS generation. While TERT knock-down abrogated Nrf2 levels, overexpression of Nrf2 increased TERT expression. Inhibition of hTERT either by Costunolide, or by siRNA or dominant-negative hTERT (DN-hTERT) abrogated (i) expression of Glucose-6-phosphate dehydrogenase (G6PD) and Transketolase (TKT) – two major nodes in the pentose phosphate (PPP) pathway; and (ii) phosphorylation of glycogen synthase (GS). hTERT knock-down decreased TKT activity and increased glycogen accumulation. Interestingly, siRNA-mediated knock-down of TKT elevated glycogen accumulation. Coherent with the
in vitro
findings, Costunolide reduced tumor burden in heterotypic xenograft glioma mouse model. Costunolide-treated tumors exhibited diminished TKT activity, heightened glycogen accumulation, and increased senescence. Importantly, glioblastoma multiforme (GBM) patient tumors bearing TERT promoter mutations (C228T and C250T) known to be associated with increased telomerase activity; exhibited elevated Nrf2 and TKT expression and decreased glycogen accumulation. Taken together, our findings highlight the previously unknown (i) role of telomerase in the regulation of PPP and glycogen accumulation and (ii) the involvement of Nrf2-TERT loop in maintaining oxidative defense responses in glioma cells.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>27148686</pmid><doi>10.1038/cddis.2016.117</doi><oa>free_for_read</oa></addata></record> |
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| subjects | 13 13/109 13/2 38 38/77 631/45/612/1245 631/67/1922 631/67/2327 631/80/86 64 64/60 82 82/29 Animals Antibodies Antineoplastic Agents, Phytogenic - pharmacology Biochemistry Biomedical and Life Sciences Brain Neoplasms - drug therapy Brain Neoplasms - genetics Brain Neoplasms - metabolism Brain Neoplasms - pathology Cell Biology Cell Culture Cell Line, Tumor Cellular Senescence - drug effects Gene Expression Regulation, Neoplastic Glioblastoma - drug therapy Glioblastoma - genetics Glioblastoma - metabolism Glioblastoma - pathology Glucosephosphate Dehydrogenase - genetics Glucosephosphate Dehydrogenase - metabolism Glycogen - biosynthesis Glycogen Synthase - genetics Glycogen Synthase - metabolism Humans Immunology Life Sciences Metabolism Mice Mice, Nude NF-E2-Related Factor 2 - antagonists & inhibitors NF-E2-Related Factor 2 - genetics NF-E2-Related Factor 2 - metabolism Original original-article Pentose Phosphate Pathway - drug effects Pentose Phosphate Pathway - genetics Phosphates Phosphorylation - drug effects Reactive Oxygen Species - agonists Reactive Oxygen Species - metabolism RNA, Small Interfering - genetics RNA, Small Interfering - metabolism Sesquiterpenes - pharmacology Signal Transduction Telomerase Telomerase - genetics Telomerase - metabolism Transketolase - antagonists & inhibitors Transketolase - genetics Transketolase - metabolism Tumor Suppressor Protein p53 - genetics Tumor Suppressor Protein p53 - metabolism Xenograft Model Antitumor Assays |
| title | Nrf2-driven TERT regulates pentose phosphate pathway in glioblastoma |
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