Glucose-regulated protein 78 (Grp78) confers chemoresistance to tumor endothelial cells under acidic stress

Detalhes bibliográficos
Autor(a) principal: Visioli, Fernanda
Data de Publicação: 2014
Outros Autores: Wang, Yugang, Alam, Goleeta N., Ning, Yu, Rados, Pantelis Varvaki, Nor, Jacques Eduardo, Polverini, Peter J.
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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spelling 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
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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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