Proteomic analysis of INS-1 rat insulinoma cells: ER stress effects and the protective role of exenatide, a GLP-1 receptor agonist
Beta cell death caused by endoplasmic reticulum (ER) stress is a key factor aggravating type 2 diabetes. Exenatide, a glucagon-like peptide (GLP)-1 receptor agonist, prevents beta cell death induced by thapsigargin, a selective inhibitor of ER calcium storage. Here, we report on our proteomic studie...
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| description | Beta cell death caused by endoplasmic reticulum (ER) stress is a key factor aggravating type 2 diabetes. Exenatide, a glucagon-like peptide (GLP)-1 receptor agonist, prevents beta cell death induced by thapsigargin, a selective inhibitor of ER calcium storage. Here, we report on our proteomic studies designed to elucidate the underlying mechanisms. We conducted comparative proteomic analyses of cellular protein profiles during thapsigargin-induced cell death in the absence and presence of exenatide in INS-1 rat insulinoma cells. Thapsigargin altered cellular proteins involved in metabolic processes and protein folding, whose alterations were variably modified by exenatide treatment. We categorized the proteins with thapsigargin initiated alterations into three groups: those whose alterations were 1) reversed by exenatide, 2) exaggerated by exenatide, and 3) unchanged by exenatide. The most significant effect of thapsigargin on INS-1 cells relevant to their apoptosis was the appearance of newly modified spots of heat shock proteins, thimet oligopeptidase and 14-3-3β, ε, and θ, and the prevention of their appearance by exenatide, suggesting that these proteins play major roles. We also found that various modifications in 14-3-3 isoforms, which precede their appearance and promote INS-1 cell death. This study provides insights into the mechanisms in ER stress-caused INS-1 cell death and its prevention by exenatide. |
| doi_str_mv | 10.1371/journal.pone.0120536 |
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Exenatide, a glucagon-like peptide (GLP)-1 receptor agonist, prevents beta cell death induced by thapsigargin, a selective inhibitor of ER calcium storage. Here, we report on our proteomic studies designed to elucidate the underlying mechanisms. We conducted comparative proteomic analyses of cellular protein profiles during thapsigargin-induced cell death in the absence and presence of exenatide in INS-1 rat insulinoma cells. Thapsigargin altered cellular proteins involved in metabolic processes and protein folding, whose alterations were variably modified by exenatide treatment. We categorized the proteins with thapsigargin initiated alterations into three groups: those whose alterations were 1) reversed by exenatide, 2) exaggerated by exenatide, and 3) unchanged by exenatide. The most significant effect of thapsigargin on INS-1 cells relevant to their apoptosis was the appearance of newly modified spots of heat shock proteins, thimet oligopeptidase and 14-3-3β, ε, and θ, and the prevention of their appearance by exenatide, suggesting that these proteins play major roles. We also found that various modifications in 14-3-3 isoforms, which precede their appearance and promote INS-1 cell death. This study provides insights into the mechanisms in ER stress-caused INS-1 cell death and its prevention by exenatide.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0120536</identifier><identifier>PMID: 25793496</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>14-3-3 protein ; 14-3-3 Proteins - metabolism ; Animals ; Antidiabetics ; Apoptosis ; Beta cells ; Calcium ; Cell culture ; Cell death ; Cell Death - drug effects ; Cell Line ; Comparative analysis ; Diabetes ; Diabetes mellitus ; Diabetes mellitus (non-insulin dependent) ; Endoplasmic reticulum ; Endoplasmic Reticulum Stress - drug effects ; GLP-1 receptor agonists ; Glucagon ; Glucagon-Like Peptide-1 Receptor - agonists ; Glucose ; Heat shock proteins ; Hypoglycemic agents ; Insulin ; Insulinoma ; Insulinoma - metabolism ; Isoforms ; Kinases ; Mass spectrometry ; Mortality ; Neuroendocrine tumors ; Oligopeptidase ; Pancreatic Neoplasms - metabolism ; Peptides ; Peptides - pharmacology ; Pharmaceutical sciences ; Pharmacy ; Phosphorylation ; Prevention ; Protein folding ; Protein Interaction Maps ; Protein Processing, Post-Translational - drug effects ; Proteins ; Proteome ; Proteomics ; Rats ; Rodents ; Scientific imaging ; Stress ; Stresses ; Thapsigargin ; Thapsigargin - pharmacology ; Thimet oligopeptidase ; Type 2 diabetes ; Venoms - pharmacology</subject><ispartof>PloS one, 2015-03, Vol.10 (3), p.e0120536-e0120536</ispartof><rights>COPYRIGHT 2015 Public Library of Science</rights><rights>2015 Kim 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>2015 Kim et al 2015 Kim et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-9c561ecb807c6e08930c08b9ea3425b075809fd4c71bc2504e6a5aea914400523</citedby><cites>FETCH-LOGICAL-c692t-9c561ecb807c6e08930c08b9ea3425b075809fd4c71bc2504e6a5aea914400523</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/PMC4368701/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4368701/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23847,27903,27904,53769,53771,79346,79347</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25793496$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Obukhov, Alexander G</contributor><creatorcontrib>Kim, Mi-Kyung</creatorcontrib><creatorcontrib>Cho, Jin-Hwan</creatorcontrib><creatorcontrib>Lee, Jae-Jin</creatorcontrib><creatorcontrib>Son, Moon-Ho</creatorcontrib><creatorcontrib>Lee, Kong-Joo</creatorcontrib><title>Proteomic analysis of INS-1 rat insulinoma cells: ER stress effects and the protective role of exenatide, a GLP-1 receptor agonist</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Beta cell death caused by endoplasmic reticulum (ER) stress is a key factor aggravating type 2 diabetes. Exenatide, a glucagon-like peptide (GLP)-1 receptor agonist, prevents beta cell death induced by thapsigargin, a selective inhibitor of ER calcium storage. Here, we report on our proteomic studies designed to elucidate the underlying mechanisms. We conducted comparative proteomic analyses of cellular protein profiles during thapsigargin-induced cell death in the absence and presence of exenatide in INS-1 rat insulinoma cells. Thapsigargin altered cellular proteins involved in metabolic processes and protein folding, whose alterations were variably modified by exenatide treatment. We categorized the proteins with thapsigargin initiated alterations into three groups: those whose alterations were 1) reversed by exenatide, 2) exaggerated by exenatide, and 3) unchanged by exenatide. The most significant effect of thapsigargin on INS-1 cells relevant to their apoptosis was the appearance of newly modified spots of heat shock proteins, thimet oligopeptidase and 14-3-3β, ε, and θ, and the prevention of their appearance by exenatide, suggesting that these proteins play major roles. We also found that various modifications in 14-3-3 isoforms, which precede their appearance and promote INS-1 cell death. This study provides insights into the mechanisms in ER stress-caused INS-1 cell death and its prevention by exenatide.</description><subject>14-3-3 protein</subject><subject>14-3-3 Proteins - metabolism</subject><subject>Animals</subject><subject>Antidiabetics</subject><subject>Apoptosis</subject><subject>Beta cells</subject><subject>Calcium</subject><subject>Cell culture</subject><subject>Cell death</subject><subject>Cell Death - drug effects</subject><subject>Cell Line</subject><subject>Comparative analysis</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>Diabetes mellitus (non-insulin dependent)</subject><subject>Endoplasmic reticulum</subject><subject>Endoplasmic Reticulum Stress - drug effects</subject><subject>GLP-1 receptor agonists</subject><subject>Glucagon</subject><subject>Glucagon-Like Peptide-1 Receptor - agonists</subject><subject>Glucose</subject><subject>Heat shock proteins</subject><subject>Hypoglycemic agents</subject><subject>Insulin</subject><subject>Insulinoma</subject><subject>Insulinoma - metabolism</subject><subject>Isoforms</subject><subject>Kinases</subject><subject>Mass spectrometry</subject><subject>Mortality</subject><subject>Neuroendocrine tumors</subject><subject>Oligopeptidase</subject><subject>Pancreatic Neoplasms - metabolism</subject><subject>Peptides</subject><subject>Peptides - pharmacology</subject><subject>Pharmaceutical sciences</subject><subject>Pharmacy</subject><subject>Phosphorylation</subject><subject>Prevention</subject><subject>Protein folding</subject><subject>Protein Interaction Maps</subject><subject>Protein Processing, Post-Translational - drug effects</subject><subject>Proteins</subject><subject>Proteome</subject><subject>Proteomics</subject><subject>Rats</subject><subject>Rodents</subject><subject>Scientific imaging</subject><subject>Stress</subject><subject>Stresses</subject><subject>Thapsigargin</subject><subject>Thapsigargin - pharmacology</subject><subject>Thimet oligopeptidase</subject><subject>Type 2 diabetes</subject><subject>Venoms - pharmacology</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNk9Fu0zAUhiMEYmPwBggsTUIg0WLHjhNzgTRNY1Sq2LQBt9apc9J6SuNiO9N2y5PjrN3Uol2gXCRyvv-zj-2TZa8ZHTNesk9XrvcdtOOV63BMWU4LLp9k-0zxfCRzyp9ufe9lL0K4ogmppHye7eVFqbhQcj_7c-5dRLe0hkCy3QYbiGvI5PvliBEPkdgu9K3t3BKIwbYNn8nJBQnRYwgEmwZNDClZk7hAshpcJtprJN61OIjwBjuItsaPBMjp9HywosFVdJ7A3HU2xJfZswbagK8274Ps59eTH8ffRtOz08nx0XRkpMrjSJlCMjSzipZGIq0Up4ZWM4XARV7MaFlUVDW1MCWbmbygAiUUgKCYEKnynB9kb9feVeuC3mxf0ExKoTijSiRisiZqB1d65e0S_K12YPXdgPNzDT5a02JKKQM5BSwUCiMloCmgNE1VM1POkCfXl81s_WyJtcEuemh3pLt_OrvQc3etBZdVSVkSvN8IvPvdY4h6acNwBNCh6-_WLXMlWCkTevgP-nh1G2oOqQDbNS7NawapPhI5rwqVyypR40eo9NSYLkm6a41N4zuBDzuBxES8iXPoQ9CTy4v_Z89-7bLvttgFQhsXwbV9tK4Lu6BYg8a7EDw2D5vMqB5a5X439NAqetMqKfZm-4AeQve9wf8CvYYOJg</recordid><startdate>20150320</startdate><enddate>20150320</enddate><creator>Kim, Mi-Kyung</creator><creator>Cho, Jin-Hwan</creator><creator>Lee, Jae-Jin</creator><creator>Son, Moon-Ho</creator><creator>Lee, Kong-Joo</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>20150320</creationdate><title>Proteomic analysis of INS-1 rat insulinoma cells: ER stress effects and the protective role of exenatide, a GLP-1 receptor agonist</title><author>Kim, Mi-Kyung ; Cho, Jin-Hwan ; Lee, Jae-Jin ; Son, Moon-Ho ; Lee, Kong-Joo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-9c561ecb807c6e08930c08b9ea3425b075809fd4c71bc2504e6a5aea914400523</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>14-3-3 protein</topic><topic>14-3-3 Proteins - metabolism</topic><topic>Animals</topic><topic>Antidiabetics</topic><topic>Apoptosis</topic><topic>Beta cells</topic><topic>Calcium</topic><topic>Cell culture</topic><topic>Cell death</topic><topic>Cell Death - drug effects</topic><topic>Cell Line</topic><topic>Comparative analysis</topic><topic>Diabetes</topic><topic>Diabetes mellitus</topic><topic>Diabetes mellitus (non-insulin dependent)</topic><topic>Endoplasmic reticulum</topic><topic>Endoplasmic Reticulum Stress - drug effects</topic><topic>GLP-1 receptor agonists</topic><topic>Glucagon</topic><topic>Glucagon-Like Peptide-1 Receptor - agonists</topic><topic>Glucose</topic><topic>Heat shock proteins</topic><topic>Hypoglycemic agents</topic><topic>Insulin</topic><topic>Insulinoma</topic><topic>Insulinoma - metabolism</topic><topic>Isoforms</topic><topic>Kinases</topic><topic>Mass spectrometry</topic><topic>Mortality</topic><topic>Neuroendocrine tumors</topic><topic>Oligopeptidase</topic><topic>Pancreatic Neoplasms - metabolism</topic><topic>Peptides</topic><topic>Peptides - 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Exenatide, a glucagon-like peptide (GLP)-1 receptor agonist, prevents beta cell death induced by thapsigargin, a selective inhibitor of ER calcium storage. Here, we report on our proteomic studies designed to elucidate the underlying mechanisms. We conducted comparative proteomic analyses of cellular protein profiles during thapsigargin-induced cell death in the absence and presence of exenatide in INS-1 rat insulinoma cells. Thapsigargin altered cellular proteins involved in metabolic processes and protein folding, whose alterations were variably modified by exenatide treatment. We categorized the proteins with thapsigargin initiated alterations into three groups: those whose alterations were 1) reversed by exenatide, 2) exaggerated by exenatide, and 3) unchanged by exenatide. The most significant effect of thapsigargin on INS-1 cells relevant to their apoptosis was the appearance of newly modified spots of heat shock proteins, thimet oligopeptidase and 14-3-3β, ε, and θ, and the prevention of their appearance by exenatide, suggesting that these proteins play major roles. We also found that various modifications in 14-3-3 isoforms, which precede their appearance and promote INS-1 cell death. This study provides insights into the mechanisms in ER stress-caused INS-1 cell death and its prevention by exenatide.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25793496</pmid><doi>10.1371/journal.pone.0120536</doi><oa>free_for_read</oa></addata></record> |
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| subjects | 14-3-3 protein 14-3-3 Proteins - metabolism Animals Antidiabetics Apoptosis Beta cells Calcium Cell culture Cell death Cell Death - drug effects Cell Line Comparative analysis Diabetes Diabetes mellitus Diabetes mellitus (non-insulin dependent) Endoplasmic reticulum Endoplasmic Reticulum Stress - drug effects GLP-1 receptor agonists Glucagon Glucagon-Like Peptide-1 Receptor - agonists Glucose Heat shock proteins Hypoglycemic agents Insulin Insulinoma Insulinoma - metabolism Isoforms Kinases Mass spectrometry Mortality Neuroendocrine tumors Oligopeptidase Pancreatic Neoplasms - metabolism Peptides Peptides - pharmacology Pharmaceutical sciences Pharmacy Phosphorylation Prevention Protein folding Protein Interaction Maps Protein Processing, Post-Translational - drug effects Proteins Proteome Proteomics Rats Rodents Scientific imaging Stress Stresses Thapsigargin Thapsigargin - pharmacology Thimet oligopeptidase Type 2 diabetes Venoms - pharmacology |
| title | Proteomic analysis of INS-1 rat insulinoma cells: ER stress effects and the protective role of exenatide, a GLP-1 receptor agonist |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-27T19%3A55%3A45IST&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=Proteomic%20analysis%20of%20INS-1%20rat%20insulinoma%20cells:%20ER%20stress%20effects%20and%20the%20protective%20role%20of%20exenatide,%20a%20GLP-1%20receptor%20agonist&rft.jtitle=PloS%20one&rft.au=Kim,%20Mi-Kyung&rft.date=2015-03-20&rft.volume=10&rft.issue=3&rft.spage=e0120536&rft.epage=e0120536&rft.pages=e0120536-e0120536&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0120536&rft_dat=%3Cgale_plos_%3EA423859268%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=1664931094&rft_id=info:pmid/25793496&rft_galeid=A423859268&rft_doaj_id=oai_doaj_org_article_169ca20ae59e4c66aec5a7cf8d1c7be3&rfr_iscdi=true |