Resistance to paclitaxel in a cisplatin-resistant ovarian cancer cell line is mediated by P-glycoprotein
The IGROVCDDP cisplatin-resistant ovarian cancer cell line is also resistant to paclitaxel and models the resistance phenotype of relapsed ovarian cancer patients after first-line platinum/taxane chemotherapy. A TaqMan low-density array (TLDA) was used to characterise the expression of 380 genes ass...
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| description | The IGROVCDDP cisplatin-resistant ovarian cancer cell line is also resistant to paclitaxel and models the resistance phenotype of relapsed ovarian cancer patients after first-line platinum/taxane chemotherapy. A TaqMan low-density array (TLDA) was used to characterise the expression of 380 genes associated with chemotherapy resistance in IGROVCDDP cells. Paclitaxel resistance in IGROVCDDP is mediated by gene and protein overexpression of P-glycoprotein and the protein is functionally active. Cisplatin resistance was not reversed by elacridar, confirming that cisplatin is not a P-glycoprotein substrate. Cisplatin resistance in IGROVCDDP is multifactorial and is mediated in part by the glutathione pathway and decreased accumulation of drug. Total cellular glutathione was not increased. However, the enzyme activity of GSR and GGT1 were up-regulated. The cellular localisation of copper transporter CTR1 changed from membrane associated in IGROV-1 to cytoplasmic in IGROVCDDP. This may mediate the previously reported accumulation defect. There was decreased expression of the sodium potassium pump (ATP1A), MRP1 and FBP which all have been previously associated with platinum accumulation defects in platinum-resistant cell lines. Cellular localisation of MRP1 was also altered in IGROVCDDP shifting basolaterally, compared to IGROV-1. BRCA1 was also up-regulated at the gene and protein level. The overexpression of P-glycoprotein in a resistant model developed with cisplatin is unusual. This demonstrates that P-glycoprotein can be up-regulated as a generalised stress response rather than as a specific response to a substrate. Mechanisms characterised in IGROVCDDP cells may be applicable to relapsed ovarian cancer patients treated with frontline platinum/taxane chemotherapy. |
| doi_str_mv | 10.1371/journal.pone.0040717 |
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A TaqMan low-density array (TLDA) was used to characterise the expression of 380 genes associated with chemotherapy resistance in IGROVCDDP cells. Paclitaxel resistance in IGROVCDDP is mediated by gene and protein overexpression of P-glycoprotein and the protein is functionally active. Cisplatin resistance was not reversed by elacridar, confirming that cisplatin is not a P-glycoprotein substrate. Cisplatin resistance in IGROVCDDP is multifactorial and is mediated in part by the glutathione pathway and decreased accumulation of drug. Total cellular glutathione was not increased. However, the enzyme activity of GSR and GGT1 were up-regulated. The cellular localisation of copper transporter CTR1 changed from membrane associated in IGROV-1 to cytoplasmic in IGROVCDDP. This may mediate the previously reported accumulation defect. There was decreased expression of the sodium potassium pump (ATP1A), MRP1 and FBP which all have been previously associated with platinum accumulation defects in platinum-resistant cell lines. Cellular localisation of MRP1 was also altered in IGROVCDDP shifting basolaterally, compared to IGROV-1. BRCA1 was also up-regulated at the gene and protein level. The overexpression of P-glycoprotein in a resistant model developed with cisplatin is unusual. This demonstrates that P-glycoprotein can be up-regulated as a generalised stress response rather than as a specific response to a substrate. Mechanisms characterised in IGROVCDDP cells may be applicable to relapsed ovarian cancer patients treated with frontline platinum/taxane chemotherapy.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0040717</identifier><identifier>PMID: 22792399</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Accumulation ; Adenosine triphosphatase ; Analysis ; Antineoplastic Agents - pharmacology ; Apoptosis ; ATP Binding Cassette Transporter, Subfamily B - genetics ; ATP Binding Cassette Transporter, Subfamily B - metabolism ; Biology ; Biomarkers - metabolism ; Biotechnology ; BRCA1 protein ; Breast cancer ; Cancer ; Cancer therapies ; Cation Transport Proteins - metabolism ; Cell Line, Tumor ; Cellular stress response ; Chemistry ; Chemoresistance ; Chemotherapy ; Cisplatin ; Cisplatin - pharmacology ; Copper ; Copper Transporter 1 ; Cytotoxicity ; Drug resistance ; Drug Resistance, Neoplasm - genetics ; Enzymatic activity ; Enzyme activity ; Enzymes ; Female ; Gene expression ; Gene Expression Regulation, Neoplastic - drug effects ; Genes ; Genes, BRCA1 ; Genetic aspects ; Glutathione ; Glutathione - metabolism ; Glycoproteins ; Hematology ; Histopathology ; Humans ; Laboratories ; Medical prognosis ; Medical research ; Medicine ; Metabolic Networks and Pathways ; Ovarian cancer ; Ovarian carcinoma ; Ovarian Neoplasms - genetics ; Ovarian Neoplasms - metabolism ; P-Glycoprotein ; Paclitaxel ; Paclitaxel - pharmacology ; Patients ; Phenotypes ; Platinum ; Position (location) ; Potassium ; Protein expression ; Proteins ; Sodium ; Substrates ; Systematic review ; Taxane ; Taxanes ; Transporter</subject><ispartof>PloS one, 2012-07, Vol.7 (7), p.e40717</ispartof><rights>COPYRIGHT 2012 Public Library of Science</rights><rights>2012. This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. 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A TaqMan low-density array (TLDA) was used to characterise the expression of 380 genes associated with chemotherapy resistance in IGROVCDDP cells. Paclitaxel resistance in IGROVCDDP is mediated by gene and protein overexpression of P-glycoprotein and the protein is functionally active. Cisplatin resistance was not reversed by elacridar, confirming that cisplatin is not a P-glycoprotein substrate. Cisplatin resistance in IGROVCDDP is multifactorial and is mediated in part by the glutathione pathway and decreased accumulation of drug. Total cellular glutathione was not increased. However, the enzyme activity of GSR and GGT1 were up-regulated. The cellular localisation of copper transporter CTR1 changed from membrane associated in IGROV-1 to cytoplasmic in IGROVCDDP. This may mediate the previously reported accumulation defect. There was decreased expression of the sodium potassium pump (ATP1A), MRP1 and FBP which all have been previously associated with platinum accumulation defects in platinum-resistant cell lines. Cellular localisation of MRP1 was also altered in IGROVCDDP shifting basolaterally, compared to IGROV-1. BRCA1 was also up-regulated at the gene and protein level. The overexpression of P-glycoprotein in a resistant model developed with cisplatin is unusual. This demonstrates that P-glycoprotein can be up-regulated as a generalised stress response rather than as a specific response to a substrate. Mechanisms characterised in IGROVCDDP cells may be applicable to relapsed ovarian cancer patients treated with frontline platinum/taxane chemotherapy.</description><subject>Accumulation</subject><subject>Adenosine triphosphatase</subject><subject>Analysis</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Apoptosis</subject><subject>ATP Binding Cassette Transporter, Subfamily B - genetics</subject><subject>ATP Binding Cassette Transporter, Subfamily B - metabolism</subject><subject>Biology</subject><subject>Biomarkers - metabolism</subject><subject>Biotechnology</subject><subject>BRCA1 protein</subject><subject>Breast cancer</subject><subject>Cancer</subject><subject>Cancer therapies</subject><subject>Cation Transport Proteins - metabolism</subject><subject>Cell Line, Tumor</subject><subject>Cellular stress response</subject><subject>Chemistry</subject><subject>Chemoresistance</subject><subject>Chemotherapy</subject><subject>Cisplatin</subject><subject>Cisplatin - pharmacology</subject><subject>Copper</subject><subject>Copper Transporter 1</subject><subject>Cytotoxicity</subject><subject>Drug resistance</subject><subject>Drug Resistance, Neoplasm - genetics</subject><subject>Enzymatic activity</subject><subject>Enzyme activity</subject><subject>Enzymes</subject><subject>Female</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Genes</subject><subject>Genes, BRCA1</subject><subject>Genetic aspects</subject><subject>Glutathione</subject><subject>Glutathione - metabolism</subject><subject>Glycoproteins</subject><subject>Hematology</subject><subject>Histopathology</subject><subject>Humans</subject><subject>Laboratories</subject><subject>Medical prognosis</subject><subject>Medical research</subject><subject>Medicine</subject><subject>Metabolic Networks and Pathways</subject><subject>Ovarian cancer</subject><subject>Ovarian carcinoma</subject><subject>Ovarian Neoplasms - genetics</subject><subject>Ovarian Neoplasms - metabolism</subject><subject>P-Glycoprotein</subject><subject>Paclitaxel</subject><subject>Paclitaxel - pharmacology</subject><subject>Patients</subject><subject>Phenotypes</subject><subject>Platinum</subject><subject>Position (location)</subject><subject>Potassium</subject><subject>Protein expression</subject><subject>Proteins</subject><subject>Sodium</subject><subject>Substrates</subject><subject>Systematic review</subject><subject>Taxane</subject><subject>Taxanes</subject><subject>Transporter</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNkl1rHCEYhYfS0ny0_6C0QiHQi9mqM6PjTSGEfiwEUtLQW1HH2XVxdapOyP77ut1J2IEWiheKPue8-nqK4g2CC1RR9HHjx-CEXQze6QWENaSIPitOEatwSTCsnh-tT4qzGDcQNlVLyMviBGPKcMXYabG-1dHEJJzSIHkwCGVNEg_aAuOAAMrEwYpkXBkmLgF_L4IRDqi9KAClrQXWOA1MBFvdGZF0B-QOfC9Xdqf8EHzSxr0qXvTCRv16ms-Luy-f766-ldc3X5dXl9elaiFLZYsgEpAgKZmGrGmhbDsKVSepJAoTQlqpGKFdjRAmrGm6NvNEQYyhVBRV58W7g-1gfeRTjyJHFW5q1rY1zsTyQHRebPgQzFaEHffC8D8bPqy4CMkoqznMpTvIeqp7WjcYsQbWHWwoI1hKQUn2-jRVG2V-utIuBWFnpvMTZ9Z85e95VbE6_1c2eD8ZBP9r1DH948oTtRL5Vsb1PpuprYmKX9aUIrS3y9TiL1Qend4alVPSm7w_E3yYCTKT9ENaiTFGvvxx-__szc85e3HErrWwaR29HZPxLs7B-gCq4GMMun_qHIJ8H_LHbvB9yPkU8ix7e9z1J9Fjqqvfz232lA</recordid><startdate>20120711</startdate><enddate>20120711</enddate><creator>Stordal, Britta</creator><creator>Hamon, Marion</creator><creator>McEneaney, Victoria</creator><creator>Roche, Sandra</creator><creator>Gillet, Jean-Pierre</creator><creator>O'Leary, John J</creator><creator>Gottesman, Michael</creator><creator>Clynes, Martin</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>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20120711</creationdate><title>Resistance to paclitaxel in a cisplatin-resistant ovarian cancer cell line is mediated by P-glycoprotein</title><author>Stordal, Britta ; Hamon, Marion ; McEneaney, Victoria ; Roche, Sandra ; Gillet, Jean-Pierre ; O'Leary, John J ; Gottesman, Michael ; Clynes, Martin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c809t-8101a061bb9e09580b8d70cdb7b6c26668bc967d41126955d801a6c0220bc713</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Accumulation</topic><topic>Adenosine triphosphatase</topic><topic>Analysis</topic><topic>Antineoplastic Agents - 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A TaqMan low-density array (TLDA) was used to characterise the expression of 380 genes associated with chemotherapy resistance in IGROVCDDP cells. Paclitaxel resistance in IGROVCDDP is mediated by gene and protein overexpression of P-glycoprotein and the protein is functionally active. Cisplatin resistance was not reversed by elacridar, confirming that cisplatin is not a P-glycoprotein substrate. Cisplatin resistance in IGROVCDDP is multifactorial and is mediated in part by the glutathione pathway and decreased accumulation of drug. Total cellular glutathione was not increased. However, the enzyme activity of GSR and GGT1 were up-regulated. The cellular localisation of copper transporter CTR1 changed from membrane associated in IGROV-1 to cytoplasmic in IGROVCDDP. This may mediate the previously reported accumulation defect. There was decreased expression of the sodium potassium pump (ATP1A), MRP1 and FBP which all have been previously associated with platinum accumulation defects in platinum-resistant cell lines. Cellular localisation of MRP1 was also altered in IGROVCDDP shifting basolaterally, compared to IGROV-1. BRCA1 was also up-regulated at the gene and protein level. The overexpression of P-glycoprotein in a resistant model developed with cisplatin is unusual. This demonstrates that P-glycoprotein can be up-regulated as a generalised stress response rather than as a specific response to a substrate. Mechanisms characterised in IGROVCDDP cells may be applicable to relapsed ovarian cancer patients treated with frontline platinum/taxane chemotherapy.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>22792399</pmid><doi>10.1371/journal.pone.0040717</doi><tpages>e40717</tpages><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_plos_journals_1325498842 |
| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Accumulation Adenosine triphosphatase Analysis Antineoplastic Agents - pharmacology Apoptosis ATP Binding Cassette Transporter, Subfamily B - genetics ATP Binding Cassette Transporter, Subfamily B - metabolism Biology Biomarkers - metabolism Biotechnology BRCA1 protein Breast cancer Cancer Cancer therapies Cation Transport Proteins - metabolism Cell Line, Tumor Cellular stress response Chemistry Chemoresistance Chemotherapy Cisplatin Cisplatin - pharmacology Copper Copper Transporter 1 Cytotoxicity Drug resistance Drug Resistance, Neoplasm - genetics Enzymatic activity Enzyme activity Enzymes Female Gene expression Gene Expression Regulation, Neoplastic - drug effects Genes Genes, BRCA1 Genetic aspects Glutathione Glutathione - metabolism Glycoproteins Hematology Histopathology Humans Laboratories Medical prognosis Medical research Medicine Metabolic Networks and Pathways Ovarian cancer Ovarian carcinoma Ovarian Neoplasms - genetics Ovarian Neoplasms - metabolism P-Glycoprotein Paclitaxel Paclitaxel - pharmacology Patients Phenotypes Platinum Position (location) Potassium Protein expression Proteins Sodium Substrates Systematic review Taxane Taxanes Transporter |
| title | Resistance to paclitaxel in a cisplatin-resistant ovarian cancer cell line is mediated by P-glycoprotein |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-12T08%3A46%3A43IST&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=Resistance%20to%20paclitaxel%20in%20a%20cisplatin-resistant%20ovarian%20cancer%20cell%20line%20is%20mediated%20by%20P-glycoprotein&rft.jtitle=PloS%20one&rft.au=Stordal,%20Britta&rft.date=2012-07-11&rft.volume=7&rft.issue=7&rft.spage=e40717&rft.pages=e40717-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0040717&rft_dat=%3Cgale_plos_%3EA477113394%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=1325498842&rft_id=info:pmid/22792399&rft_galeid=A477113394&rft_doaj_id=oai_doaj_org_article_0d70d09f7ef745219504d057962bba76&rfr_iscdi=true |