Glucose-regulated protein 78 (Grp78) confers chemoresistance to tumor endothelial cells under acidic stress
Autor(a) principal: | |
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Data de Publicação: | 2014 |
Outros Autores: | , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UFRGS |
Texto Completo: | http://hdl.handle.net/10183/104482 |
Resumo: | Objectives: This study was designed to investigate the activation of the unfolded protein response (UPR) in tumor associated endothelial cells (TECs) and its association with chemoresistance during acidic pH stress. Materials and Methods: Endothelial cells from human oral squamous cell carcinomas (OSCC) were excised by laser capture microdissection (LCM) followed by analysis of UPR markers (Grp78, ATF4 and CHOP) using quantitative PCR. Grp78 expression was also determined by immunostaining. Acidic stress was induced in primary human dermal microvascular endothelial cells (HDMECs) by treatment with conditioned medium (CM) from tumor cells grown under hypoxic conditions or by adjusting medium pH to 6.4 or 7.0 using lactic acid or hydrochloric acid (HCl). HDMEC resistance to the antiangiogenic drug Sunitinib was assessed with SRB assay. Results: UPR markers, Grp78, ATF4 and CHOP were significantly upregulated in TECs from OSCC compared to HDMECs. HDMECs cultured in acidic CM (pH 6.0–6.4) showed increased expression of the UPR markers. However, severe acidosis led to marked cell death in HDMECs. Alternatively, HDMECs were able to adapt when exposed to chronic acidosis at pH 7.0 for 7 days, with concomittant increase in Grp78 expression. Chronic acidosis also confers drug resistance to HDMECs against Sunitinib. Knockdown of Grp78 using shRNA resensitizes HDMECs to drug treatment. Conclusions: UPR induction in ECs under acidic pH conditions is related to chemoresistance and may contribute to therapeutic failures in response to chemotherapy. Targeting Grp78, the key component of the UPR pathway, may provide a promising approach to overcome ECs resistance in cancer therapy. |
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Visioli, FernandaWang, YugangAlam, Goleeta N.Ning, YuRados, Pantelis VarvakiNor, Jacques EduardoPolverini, Peter J.2014-10-11T02:11:48Z20141932-6203http://hdl.handle.net/10183/104482000922206Objectives: This study was designed to investigate the activation of the unfolded protein response (UPR) in tumor associated endothelial cells (TECs) and its association with chemoresistance during acidic pH stress. Materials and Methods: Endothelial cells from human oral squamous cell carcinomas (OSCC) were excised by laser capture microdissection (LCM) followed by analysis of UPR markers (Grp78, ATF4 and CHOP) using quantitative PCR. Grp78 expression was also determined by immunostaining. Acidic stress was induced in primary human dermal microvascular endothelial cells (HDMECs) by treatment with conditioned medium (CM) from tumor cells grown under hypoxic conditions or by adjusting medium pH to 6.4 or 7.0 using lactic acid or hydrochloric acid (HCl). HDMEC resistance to the antiangiogenic drug Sunitinib was assessed with SRB assay. Results: UPR markers, Grp78, ATF4 and CHOP were significantly upregulated in TECs from OSCC compared to HDMECs. HDMECs cultured in acidic CM (pH 6.0–6.4) showed increased expression of the UPR markers. However, severe acidosis led to marked cell death in HDMECs. Alternatively, HDMECs were able to adapt when exposed to chronic acidosis at pH 7.0 for 7 days, with concomittant increase in Grp78 expression. Chronic acidosis also confers drug resistance to HDMECs against Sunitinib. Knockdown of Grp78 using shRNA resensitizes HDMECs to drug treatment. Conclusions: UPR induction in ECs under acidic pH conditions is related to chemoresistance and may contribute to therapeutic failures in response to chemotherapy. Targeting Grp78, the key component of the UPR pathway, may provide a promising approach to overcome ECs resistance in cancer therapy.application/pdfengPLOS ONE. São Francisco. Vol. 9, no. 6 (June 2014), e101053, 9 p.Células endoteliaisNeoplasias bucaisResposta a proteínas não dobradasGlucose-regulated protein 78 (Grp78) confers chemoresistance to tumor endothelial cells under acidic stressEstrangeiroinfo:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UFRGSinstname:Universidade Federal do Rio Grande do Sul (UFRGS)instacron:UFRGSORIGINAL000922206.pdf000922206.pdfTexto completo (inglês)application/pdf3660958http://www.lume.ufrgs.br/bitstream/10183/104482/1/000922206.pdf72c9906f298910e019146e16be88e7eaMD51TEXT000922206.pdf.txt000922206.pdf.txtExtracted Texttext/plain42007http://www.lume.ufrgs.br/bitstream/10183/104482/2/000922206.pdf.txt14d16076e522aafa16b0f3990af38f41MD52THUMBNAIL000922206.pdf.jpg000922206.pdf.jpgGenerated Thumbnailimage/jpeg2216http://www.lume.ufrgs.br/bitstream/10183/104482/3/000922206.pdf.jpg115e4e344a679e2db947480d48474406MD5310183/1044822023-09-23 03:36:41.845849oai:www.lume.ufrgs.br:10183/104482Repositório de PublicaçõesPUBhttps://lume.ufrgs.br/oai/requestopendoar:2023-09-23T06:36:41Repositório Institucional da UFRGS - Universidade Federal do Rio Grande do Sul (UFRGS)false |
dc.title.pt_BR.fl_str_mv |
Glucose-regulated protein 78 (Grp78) confers chemoresistance to tumor endothelial cells under acidic stress |
title |
Glucose-regulated protein 78 (Grp78) confers chemoresistance to tumor endothelial cells under acidic stress |
spellingShingle |
Glucose-regulated protein 78 (Grp78) confers chemoresistance to tumor endothelial cells under acidic stress Visioli, Fernanda Células endoteliais Neoplasias bucais Resposta a proteínas não dobradas |
title_short |
Glucose-regulated protein 78 (Grp78) confers chemoresistance to tumor endothelial cells under acidic stress |
title_full |
Glucose-regulated protein 78 (Grp78) confers chemoresistance to tumor endothelial cells under acidic stress |
title_fullStr |
Glucose-regulated protein 78 (Grp78) confers chemoresistance to tumor endothelial cells under acidic stress |
title_full_unstemmed |
Glucose-regulated protein 78 (Grp78) confers chemoresistance to tumor endothelial cells under acidic stress |
title_sort |
Glucose-regulated protein 78 (Grp78) confers chemoresistance to tumor endothelial cells under acidic stress |
author |
Visioli, Fernanda |
author_facet |
Visioli, Fernanda Wang, Yugang Alam, Goleeta N. Ning, Yu Rados, Pantelis Varvaki Nor, Jacques Eduardo Polverini, Peter J. |
author_role |
author |
author2 |
Wang, Yugang Alam, Goleeta N. Ning, Yu Rados, Pantelis Varvaki Nor, Jacques Eduardo Polverini, Peter J. |
author2_role |
author author author author author author |
dc.contributor.author.fl_str_mv |
Visioli, Fernanda Wang, Yugang Alam, Goleeta N. Ning, Yu Rados, Pantelis Varvaki Nor, Jacques Eduardo Polverini, Peter J. |
dc.subject.por.fl_str_mv |
Células endoteliais Neoplasias bucais Resposta a proteínas não dobradas |
topic |
Células endoteliais Neoplasias bucais Resposta a proteínas não dobradas |
description |
Objectives: This study was designed to investigate the activation of the unfolded protein response (UPR) in tumor associated endothelial cells (TECs) and its association with chemoresistance during acidic pH stress. Materials and Methods: Endothelial cells from human oral squamous cell carcinomas (OSCC) were excised by laser capture microdissection (LCM) followed by analysis of UPR markers (Grp78, ATF4 and CHOP) using quantitative PCR. Grp78 expression was also determined by immunostaining. Acidic stress was induced in primary human dermal microvascular endothelial cells (HDMECs) by treatment with conditioned medium (CM) from tumor cells grown under hypoxic conditions or by adjusting medium pH to 6.4 or 7.0 using lactic acid or hydrochloric acid (HCl). HDMEC resistance to the antiangiogenic drug Sunitinib was assessed with SRB assay. Results: UPR markers, Grp78, ATF4 and CHOP were significantly upregulated in TECs from OSCC compared to HDMECs. HDMECs cultured in acidic CM (pH 6.0–6.4) showed increased expression of the UPR markers. However, severe acidosis led to marked cell death in HDMECs. Alternatively, HDMECs were able to adapt when exposed to chronic acidosis at pH 7.0 for 7 days, with concomittant increase in Grp78 expression. Chronic acidosis also confers drug resistance to HDMECs against Sunitinib. Knockdown of Grp78 using shRNA resensitizes HDMECs to drug treatment. Conclusions: UPR induction in ECs under acidic pH conditions is related to chemoresistance and may contribute to therapeutic failures in response to chemotherapy. Targeting Grp78, the key component of the UPR pathway, may provide a promising approach to overcome ECs resistance in cancer therapy. |
publishDate |
2014 |
dc.date.accessioned.fl_str_mv |
2014-10-11T02:11:48Z |
dc.date.issued.fl_str_mv |
2014 |
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Estrangeiro info:eu-repo/semantics/article |
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http://hdl.handle.net/10183/104482 |
dc.identifier.issn.pt_BR.fl_str_mv |
1932-6203 |
dc.identifier.nrb.pt_BR.fl_str_mv |
000922206 |
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1932-6203 000922206 |
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http://hdl.handle.net/10183/104482 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.ispartof.pt_BR.fl_str_mv |
PLOS ONE. São Francisco. Vol. 9, no. 6 (June 2014), e101053, 9 p. |
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openAccess |
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