GSK3A is redundant with GSK3B in modulating drug resistance and chemotherapy-induced necroptosis
Glycogen Synthase Kinase-3 alpha (GSK3A) and beta (GSK3B) isoforms are encoded by distinct genes, are 98% identical within their kinase domain and perform similar functions in several settings; however, they are not completely redundant and, depending on the cell type and differentiative status, the...
Gespeichert in:
| Veröffentlicht in: | PloS one 2014-07, Vol.9 (7), p.e100947-e100947 |
|---|---|
| Hauptverfasser: | , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | e100947 |
|---|---|
| container_issue | 7 |
| container_start_page | e100947 |
| container_title | PloS one |
| container_volume | 9 |
| creator | Grassilli, Emanuela Ianzano, Leonarda Bonomo, Sara Missaglia, Carola Cerrito, Maria Grazia Giovannoni, Roberto Masiero, Laura Lavitrano, Marialuisa |
| description | Glycogen Synthase Kinase-3 alpha (GSK3A) and beta (GSK3B) isoforms are encoded by distinct genes, are 98% identical within their kinase domain and perform similar functions in several settings; however, they are not completely redundant and, depending on the cell type and differentiative status, they also play unique roles. We recently identified a role for GSK3B in drug resistance by demonstrating that its inhibition enables necroptosis in response to chemotherapy in p53-null drug-resistant colon carcinoma cells. We report here that, similarly to GSK3B, also GSK3A silencing/inhibition does not affect cell proliferation or cell cycle but only abolishes growth after treatment with DNA-damaging chemotherapy. In particular, blocking GSK3A impairs DNA repair upon exposure to DNA-damaging drugs. As a consequence, p53-null cells overcome their inability to undergo apoptosis and mount a necroptotic response, characterized by absence of caspase activation and RIP1-independent, PARP-dependent AIF nuclear re-localization. We therefore conclude that GSK3A is redundant with GSK3B in regulating drug-resistance and chemotherapy-induced necroptosis and suggest that inhibition of only one isoform, or rather partial inhibition of overall cellular GSK3 activity, is enough to re-sensitize drug-resistant cells to chemotherapy. |
| doi_str_mv | 10.1371/journal.pone.0100947 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_plos_</sourceid><recordid>TN_cdi_plos_journals_1542040794</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A416677960</galeid><doaj_id>oai_doaj_org_article_6e39a90d1871428fb847b195443851d3</doaj_id><sourcerecordid>A416677960</sourcerecordid><originalsourceid>FETCH-LOGICAL-c692t-3c6e029e312dbaf8701f104ce03e2edc1af7cae7f2b5b34032fdc6c9cf3ad9d13</originalsourceid><addsrcrecordid>eNqNk01v1DAQhiMEoqXwDxBEQkJw2MVfseML0lJBWVGpEgWuxrGdxFXWXmwH6L_Hy6bVBvWAfLA1fuad8XimKJ5CsISYwTdXfgxODsutd2YJIACcsHvFMeQYLSgC-P7B-ah4FOMVABWuKX1YHCHCawIoPi6-n11-wqvSxjIYPTotXSp_2dSXO_u70rpy4_U4yGRdV-owdpmLNibplCml06Xqzcan3gS5vV5Yp0dldOmMCn6bfCYfFw9aOUTzZNpPiq8f3n85_bg4vzhbn67OF4pylBZYUQMQNxgi3ci2ZgC2EBBlADbIaAVly5Q0rEVN1WACMGq1ooqrFkvNNcQnxfO97nbwUUzFiQJWBAECGCeZWO8J7eWV2Aa7keFaeGnFX4MPnZAhWTUYQQ3mkgMNawYJqtumJqyBvCIE1xXUOGu9naKNzSanZ1wKcpiJzm-c7UXnf4qcCmMAZYFXk0DwP0YTk9jYqMwwSGf8uM-bVojDKqMv_kHvft1EdTI_wLrW57hqJypWBFLKGKcgU8s7qLy02ViVO6m12T5zeD1zyEwyv1MnxxjF-vLz_7MX3-bsywO2N3JIffTDmKx3cQ6SPZg7KsZg2tsiQyB2g3BTDbEbBDENQnZ7dvhBt043nY__AEoUAsk</addsrcrecordid><sourcetype>Open Website</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1542040794</pqid></control><display><type>article</type><title>GSK3A is redundant with GSK3B in modulating drug resistance and chemotherapy-induced necroptosis</title><source>MEDLINE</source><source>DOAJ Directory of Open Access Journals</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>Public Library of Science (PLoS) Journals Open Access</source><source>PubMed Central</source><source>Free Full-Text Journals in Chemistry</source><creator>Grassilli, Emanuela ; Ianzano, Leonarda ; Bonomo, Sara ; Missaglia, Carola ; Cerrito, Maria Grazia ; Giovannoni, Roberto ; Masiero, Laura ; Lavitrano, Marialuisa</creator><contributor>Condorelli, Gerolama</contributor><creatorcontrib>Grassilli, Emanuela ; Ianzano, Leonarda ; Bonomo, Sara ; Missaglia, Carola ; Cerrito, Maria Grazia ; Giovannoni, Roberto ; Masiero, Laura ; Lavitrano, Marialuisa ; Condorelli, Gerolama</creatorcontrib><description>Glycogen Synthase Kinase-3 alpha (GSK3A) and beta (GSK3B) isoforms are encoded by distinct genes, are 98% identical within their kinase domain and perform similar functions in several settings; however, they are not completely redundant and, depending on the cell type and differentiative status, they also play unique roles. We recently identified a role for GSK3B in drug resistance by demonstrating that its inhibition enables necroptosis in response to chemotherapy in p53-null drug-resistant colon carcinoma cells. We report here that, similarly to GSK3B, also GSK3A silencing/inhibition does not affect cell proliferation or cell cycle but only abolishes growth after treatment with DNA-damaging chemotherapy. In particular, blocking GSK3A impairs DNA repair upon exposure to DNA-damaging drugs. As a consequence, p53-null cells overcome their inability to undergo apoptosis and mount a necroptotic response, characterized by absence of caspase activation and RIP1-independent, PARP-dependent AIF nuclear re-localization. We therefore conclude that GSK3A is redundant with GSK3B in regulating drug-resistance and chemotherapy-induced necroptosis and suggest that inhibition of only one isoform, or rather partial inhibition of overall cellular GSK3 activity, is enough to re-sensitize drug-resistant cells to chemotherapy.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0100947</identifier><identifier>PMID: 24984063</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Alzheimer's disease ; Alzheimers disease ; Apoptosis ; Apoptosis-inducing factor ; Autophagy ; Biology and Life Sciences ; Brain cancer ; Cancer therapies ; Caspase ; Cell cycle ; Cell death ; Cell Line, Tumor ; Cell proliferation ; Chemotherapy ; Coding ; Colon ; Colon cancer ; Colonic Neoplasms - drug therapy ; Colonic Neoplasms - enzymology ; Colonic Neoplasms - genetics ; Colonic Neoplasms - pathology ; Deoxyribonucleic acid ; DNA ; DNA damage ; DNA repair ; Drug resistance ; Drug Resistance, Neoplasm ; Glycogen ; Glycogen synthase kinase 3 ; Glycogen Synthase Kinase 3 - genetics ; Glycogen Synthase Kinase 3 - metabolism ; Glycogen Synthase Kinase 3 beta ; Glycogen synthesis ; Humans ; Inhibition ; Isoenzymes - genetics ; Isoenzymes - metabolism ; Isoforms ; Kinases ; Localization ; Medical schools ; Medicine ; Medicine and Health Sciences ; Melanoma ; Necroptosis ; Necrosis ; Null cells ; p53 Protein ; Pancreatic cancer ; Phosphorylation ; Poly(ADP-ribose) polymerase ; Proteins ; Redundancy ; Rodents ; Surgery ; Tumor proteins ; Tumor Suppressor Protein p53 - genetics</subject><ispartof>PloS one, 2014-07, Vol.9 (7), p.e100947-e100947</ispartof><rights>COPYRIGHT 2014 Public Library of Science</rights><rights>2014 Grassilli et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://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>2014 Grassilli et al 2014 Grassilli et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-3c6e029e312dbaf8701f104ce03e2edc1af7cae7f2b5b34032fdc6c9cf3ad9d13</citedby><cites>FETCH-LOGICAL-c692t-3c6e029e312dbaf8701f104ce03e2edc1af7cae7f2b5b34032fdc6c9cf3ad9d13</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/PMC4077702/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4077702/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79600,79601</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24984063$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Condorelli, Gerolama</contributor><creatorcontrib>Grassilli, Emanuela</creatorcontrib><creatorcontrib>Ianzano, Leonarda</creatorcontrib><creatorcontrib>Bonomo, Sara</creatorcontrib><creatorcontrib>Missaglia, Carola</creatorcontrib><creatorcontrib>Cerrito, Maria Grazia</creatorcontrib><creatorcontrib>Giovannoni, Roberto</creatorcontrib><creatorcontrib>Masiero, Laura</creatorcontrib><creatorcontrib>Lavitrano, Marialuisa</creatorcontrib><title>GSK3A is redundant with GSK3B in modulating drug resistance and chemotherapy-induced necroptosis</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Glycogen Synthase Kinase-3 alpha (GSK3A) and beta (GSK3B) isoforms are encoded by distinct genes, are 98% identical within their kinase domain and perform similar functions in several settings; however, they are not completely redundant and, depending on the cell type and differentiative status, they also play unique roles. We recently identified a role for GSK3B in drug resistance by demonstrating that its inhibition enables necroptosis in response to chemotherapy in p53-null drug-resistant colon carcinoma cells. We report here that, similarly to GSK3B, also GSK3A silencing/inhibition does not affect cell proliferation or cell cycle but only abolishes growth after treatment with DNA-damaging chemotherapy. In particular, blocking GSK3A impairs DNA repair upon exposure to DNA-damaging drugs. As a consequence, p53-null cells overcome their inability to undergo apoptosis and mount a necroptotic response, characterized by absence of caspase activation and RIP1-independent, PARP-dependent AIF nuclear re-localization. We therefore conclude that GSK3A is redundant with GSK3B in regulating drug-resistance and chemotherapy-induced necroptosis and suggest that inhibition of only one isoform, or rather partial inhibition of overall cellular GSK3 activity, is enough to re-sensitize drug-resistant cells to chemotherapy.</description><subject>Alzheimer's disease</subject><subject>Alzheimers disease</subject><subject>Apoptosis</subject><subject>Apoptosis-inducing factor</subject><subject>Autophagy</subject><subject>Biology and Life Sciences</subject><subject>Brain cancer</subject><subject>Cancer therapies</subject><subject>Caspase</subject><subject>Cell cycle</subject><subject>Cell death</subject><subject>Cell Line, Tumor</subject><subject>Cell proliferation</subject><subject>Chemotherapy</subject><subject>Coding</subject><subject>Colon</subject><subject>Colon cancer</subject><subject>Colonic Neoplasms - drug therapy</subject><subject>Colonic Neoplasms - enzymology</subject><subject>Colonic Neoplasms - genetics</subject><subject>Colonic Neoplasms - pathology</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA damage</subject><subject>DNA repair</subject><subject>Drug resistance</subject><subject>Drug Resistance, Neoplasm</subject><subject>Glycogen</subject><subject>Glycogen synthase kinase 3</subject><subject>Glycogen Synthase Kinase 3 - genetics</subject><subject>Glycogen Synthase Kinase 3 - metabolism</subject><subject>Glycogen Synthase Kinase 3 beta</subject><subject>Glycogen synthesis</subject><subject>Humans</subject><subject>Inhibition</subject><subject>Isoenzymes - genetics</subject><subject>Isoenzymes - metabolism</subject><subject>Isoforms</subject><subject>Kinases</subject><subject>Localization</subject><subject>Medical schools</subject><subject>Medicine</subject><subject>Medicine and Health Sciences</subject><subject>Melanoma</subject><subject>Necroptosis</subject><subject>Necrosis</subject><subject>Null cells</subject><subject>p53 Protein</subject><subject>Pancreatic cancer</subject><subject>Phosphorylation</subject><subject>Poly(ADP-ribose) polymerase</subject><subject>Proteins</subject><subject>Redundancy</subject><subject>Rodents</subject><subject>Surgery</subject><subject>Tumor proteins</subject><subject>Tumor Suppressor Protein p53 - genetics</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNk01v1DAQhiMEoqXwDxBEQkJw2MVfseML0lJBWVGpEgWuxrGdxFXWXmwH6L_Hy6bVBvWAfLA1fuad8XimKJ5CsISYwTdXfgxODsutd2YJIACcsHvFMeQYLSgC-P7B-ah4FOMVABWuKX1YHCHCawIoPi6-n11-wqvSxjIYPTotXSp_2dSXO_u70rpy4_U4yGRdV-owdpmLNibplCml06Xqzcan3gS5vV5Yp0dldOmMCn6bfCYfFw9aOUTzZNpPiq8f3n85_bg4vzhbn67OF4pylBZYUQMQNxgi3ci2ZgC2EBBlADbIaAVly5Q0rEVN1WACMGq1ooqrFkvNNcQnxfO97nbwUUzFiQJWBAECGCeZWO8J7eWV2Aa7keFaeGnFX4MPnZAhWTUYQQ3mkgMNawYJqtumJqyBvCIE1xXUOGu9naKNzSanZ1wKcpiJzm-c7UXnf4qcCmMAZYFXk0DwP0YTk9jYqMwwSGf8uM-bVojDKqMv_kHvft1EdTI_wLrW57hqJypWBFLKGKcgU8s7qLy02ViVO6m12T5zeD1zyEwyv1MnxxjF-vLz_7MX3-bsywO2N3JIffTDmKx3cQ6SPZg7KsZg2tsiQyB2g3BTDbEbBDENQnZ7dvhBt043nY__AEoUAsk</recordid><startdate>20140701</startdate><enddate>20140701</enddate><creator>Grassilli, Emanuela</creator><creator>Ianzano, Leonarda</creator><creator>Bonomo, Sara</creator><creator>Missaglia, Carola</creator><creator>Cerrito, Maria Grazia</creator><creator>Giovannoni, Roberto</creator><creator>Masiero, Laura</creator><creator>Lavitrano, Marialuisa</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>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>20140701</creationdate><title>GSK3A is redundant with GSK3B in modulating drug resistance and chemotherapy-induced necroptosis</title><author>Grassilli, Emanuela ; Ianzano, Leonarda ; Bonomo, Sara ; Missaglia, Carola ; Cerrito, Maria Grazia ; Giovannoni, Roberto ; Masiero, Laura ; Lavitrano, Marialuisa</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-3c6e029e312dbaf8701f104ce03e2edc1af7cae7f2b5b34032fdc6c9cf3ad9d13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Alzheimer's disease</topic><topic>Alzheimers disease</topic><topic>Apoptosis</topic><topic>Apoptosis-inducing factor</topic><topic>Autophagy</topic><topic>Biology and Life Sciences</topic><topic>Brain cancer</topic><topic>Cancer therapies</topic><topic>Caspase</topic><topic>Cell cycle</topic><topic>Cell death</topic><topic>Cell Line, Tumor</topic><topic>Cell proliferation</topic><topic>Chemotherapy</topic><topic>Coding</topic><topic>Colon</topic><topic>Colon cancer</topic><topic>Colonic Neoplasms - drug therapy</topic><topic>Colonic Neoplasms - enzymology</topic><topic>Colonic Neoplasms - genetics</topic><topic>Colonic Neoplasms - pathology</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>DNA damage</topic><topic>DNA repair</topic><topic>Drug resistance</topic><topic>Drug Resistance, Neoplasm</topic><topic>Glycogen</topic><topic>Glycogen synthase kinase 3</topic><topic>Glycogen Synthase Kinase 3 - genetics</topic><topic>Glycogen Synthase Kinase 3 - metabolism</topic><topic>Glycogen Synthase Kinase 3 beta</topic><topic>Glycogen synthesis</topic><topic>Humans</topic><topic>Inhibition</topic><topic>Isoenzymes - genetics</topic><topic>Isoenzymes - metabolism</topic><topic>Isoforms</topic><topic>Kinases</topic><topic>Localization</topic><topic>Medical schools</topic><topic>Medicine</topic><topic>Medicine and Health Sciences</topic><topic>Melanoma</topic><topic>Necroptosis</topic><topic>Necrosis</topic><topic>Null cells</topic><topic>p53 Protein</topic><topic>Pancreatic cancer</topic><topic>Phosphorylation</topic><topic>Poly(ADP-ribose) polymerase</topic><topic>Proteins</topic><topic>Redundancy</topic><topic>Rodents</topic><topic>Surgery</topic><topic>Tumor proteins</topic><topic>Tumor Suppressor Protein p53 - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Grassilli, Emanuela</creatorcontrib><creatorcontrib>Ianzano, Leonarda</creatorcontrib><creatorcontrib>Bonomo, Sara</creatorcontrib><creatorcontrib>Missaglia, Carola</creatorcontrib><creatorcontrib>Cerrito, Maria Grazia</creatorcontrib><creatorcontrib>Giovannoni, Roberto</creatorcontrib><creatorcontrib>Masiero, Laura</creatorcontrib><creatorcontrib>Lavitrano, Marialuisa</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 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 - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</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>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - 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>Grassilli, Emanuela</au><au>Ianzano, Leonarda</au><au>Bonomo, Sara</au><au>Missaglia, Carola</au><au>Cerrito, Maria Grazia</au><au>Giovannoni, Roberto</au><au>Masiero, Laura</au><au>Lavitrano, Marialuisa</au><au>Condorelli, Gerolama</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>GSK3A is redundant with GSK3B in modulating drug resistance and chemotherapy-induced necroptosis</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2014-07-01</date><risdate>2014</risdate><volume>9</volume><issue>7</issue><spage>e100947</spage><epage>e100947</epage><pages>e100947-e100947</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Glycogen Synthase Kinase-3 alpha (GSK3A) and beta (GSK3B) isoforms are encoded by distinct genes, are 98% identical within their kinase domain and perform similar functions in several settings; however, they are not completely redundant and, depending on the cell type and differentiative status, they also play unique roles. We recently identified a role for GSK3B in drug resistance by demonstrating that its inhibition enables necroptosis in response to chemotherapy in p53-null drug-resistant colon carcinoma cells. We report here that, similarly to GSK3B, also GSK3A silencing/inhibition does not affect cell proliferation or cell cycle but only abolishes growth after treatment with DNA-damaging chemotherapy. In particular, blocking GSK3A impairs DNA repair upon exposure to DNA-damaging drugs. As a consequence, p53-null cells overcome their inability to undergo apoptosis and mount a necroptotic response, characterized by absence of caspase activation and RIP1-independent, PARP-dependent AIF nuclear re-localization. We therefore conclude that GSK3A is redundant with GSK3B in regulating drug-resistance and chemotherapy-induced necroptosis and suggest that inhibition of only one isoform, or rather partial inhibition of overall cellular GSK3 activity, is enough to re-sensitize drug-resistant cells to chemotherapy.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24984063</pmid><doi>10.1371/journal.pone.0100947</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2014-07, Vol.9 (7), p.e100947-e100947 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1542040794 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS) Journals Open Access; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Alzheimer's disease Alzheimers disease Apoptosis Apoptosis-inducing factor Autophagy Biology and Life Sciences Brain cancer Cancer therapies Caspase Cell cycle Cell death Cell Line, Tumor Cell proliferation Chemotherapy Coding Colon Colon cancer Colonic Neoplasms - drug therapy Colonic Neoplasms - enzymology Colonic Neoplasms - genetics Colonic Neoplasms - pathology Deoxyribonucleic acid DNA DNA damage DNA repair Drug resistance Drug Resistance, Neoplasm Glycogen Glycogen synthase kinase 3 Glycogen Synthase Kinase 3 - genetics Glycogen Synthase Kinase 3 - metabolism Glycogen Synthase Kinase 3 beta Glycogen synthesis Humans Inhibition Isoenzymes - genetics Isoenzymes - metabolism Isoforms Kinases Localization Medical schools Medicine Medicine and Health Sciences Melanoma Necroptosis Necrosis Null cells p53 Protein Pancreatic cancer Phosphorylation Poly(ADP-ribose) polymerase Proteins Redundancy Rodents Surgery Tumor proteins Tumor Suppressor Protein p53 - genetics |
| title | GSK3A is redundant with GSK3B in modulating drug resistance and chemotherapy-induced necroptosis |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-04T09%3A06%3A31IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=GSK3A%20is%20redundant%20with%20GSK3B%20in%20modulating%20drug%20resistance%20and%20chemotherapy-induced%20necroptosis&rft.jtitle=PloS%20one&rft.au=Grassilli,%20Emanuela&rft.date=2014-07-01&rft.volume=9&rft.issue=7&rft.spage=e100947&rft.epage=e100947&rft.pages=e100947-e100947&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0100947&rft_dat=%3Cgale_plos_%3EA416677960%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1542040794&rft_id=info:pmid/24984063&rft_galeid=A416677960&rft_doaj_id=oai_doaj_org_article_6e39a90d1871428fb847b195443851d3&rfr_iscdi=true |