Glucose-regulated protein 78 (Grp78) confers chemoresistance to tumor endothelial cells under acidic stress
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. Endothelial cells from human oral squamous cell carcinomas (OSCC) were excised by laser capture...
Gespeichert in:
| Veröffentlicht in: | PloS one 2014-06, Vol.9 (6), p.e101053 |
|---|---|
| Hauptverfasser: | , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | |
|---|---|
| container_issue | 6 |
| container_start_page | e101053 |
| container_title | PloS one |
| container_volume | 9 |
| creator | Visioli, Fernanda Wang, Yugang Alam, Goleeta N Ning, Yu Rados, Pantelis V Nör, Jacques E Polverini, Peter J |
| description | 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.
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 anti-angiogenic drug Sunitinib was assessed with SRB assay.
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.
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. |
| doi_str_mv | 10.1371/journal.pone.0101053 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_plos_</sourceid><recordid>TN_cdi_plos_journals_1540471233</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A417844205</galeid><doaj_id>oai_doaj_org_article_35c807ba87ec4031a60fc8bc29c0146a</doaj_id><sourcerecordid>A417844205</sourcerecordid><originalsourceid>FETCH-LOGICAL-c659t-3fe4cc144cddc6b5915313995b302d797191ef97505519655080688e4adea3123</originalsourceid><addsrcrecordid>eNptUstuEzEUHSEQLYE_QGCJTVkk2OPHjDdIVVVCpUpsYG059p3EwbGD7UHi7-s006pBlRe27j3n3IdP07wneEFoR75s45iC9ot9DLDApB5OXzTnRNJ2LlpMXz55nzVvct7iiuiFeN2ctUwKhiU5b34v_WhihnmC9eh1AYv2KRZwAXU9ulimfdd_RiaGAVJGZgO7mCC7XHQwgEpEZawRBMHGsgHvtEcGvM9oDBYS0sZZZ1AulZTfNq8G7TO8m-5Z8-vb9c-r7_PbH8ubq8vbuRFcljkdgBlDGDPWGrHiknBKqJR8RXFrO9kRSWCQHcecEyk4xz0WfQ9MW9CUtHTWfDzq7n3MatpTVoQzzLqapxVxc0TYqLdqn9xOp38qaqfuAzGtlU7FGQ-KctPjbqX7DgzDlGiBB9OvTCsNJkzoqvV1qjaudmANhJK0PxE9zQS3Uev4VzHcEUwP7V5MAin-GSEXtXP5sEQdII73fRNaeyCiQj_9B31-ugm11nUAF4ZY65qDqLpkpOsZa6sTZs3iGVQ9FnaufjgMrsZPCOxIMCnmnGB4nJFgdbDkQzPqYEk1WbLSPjzdzyPpwYP0DmOU3PI</addsrcrecordid><sourcetype>Open Website</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1540471233</pqid></control><display><type>article</type><title>Glucose-regulated protein 78 (Grp78) confers chemoresistance to tumor endothelial cells under acidic stress</title><source>MEDLINE</source><source>DOAJ Directory of Open Access Journals</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>PubMed Central</source><source>Free Full-Text Journals in Chemistry</source><source>Public Library of Science (PLoS)</source><creator>Visioli, Fernanda ; Wang, Yugang ; Alam, Goleeta N ; Ning, Yu ; Rados, Pantelis V ; Nör, Jacques E ; Polverini, Peter J</creator><creatorcontrib>Visioli, Fernanda ; Wang, Yugang ; Alam, Goleeta N ; Ning, Yu ; Rados, Pantelis V ; Nör, Jacques E ; Polverini, Peter J</creatorcontrib><description>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.
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 anti-angiogenic drug Sunitinib was assessed with SRB assay.
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.
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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0101053</identifier><identifier>PMID: 24964091</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Acid resistance ; Acidosis ; Acidosis - drug therapy ; Acidosis - metabolism ; Acidosis - pathology ; Acids ; Analysis ; Angiogenesis ; Angiogenesis Inhibitors - pharmacology ; Apoptosis ; B cells ; Biology and Life Sciences ; Blotting, Western ; Cancer ; Cancer therapies ; Carcinoma, Squamous Cell - drug therapy ; Carcinoma, Squamous Cell - metabolism ; Carcinoma, Squamous Cell - pathology ; Cell Cycle ; Cell death ; Cell Proliferation ; Cells, Cultured ; Chemoresistance ; Chemotherapy ; Conditioning ; Cytotoxicity ; Dental materials ; Dentistry ; Dermis - drug effects ; Dermis - metabolism ; Dermis - pathology ; Drug resistance ; Drug Resistance, Neoplasm ; Endoplasmic reticulum ; Endoplasmic Reticulum Chaperone BiP ; Endothelial cells ; Endothelium ; Endothelium, Vascular - drug effects ; Endothelium, Vascular - metabolism ; Endothelium, Vascular - pathology ; Fluorescent Antibody Technique ; Glucose ; Glycoproteins ; Head & neck cancer ; Heat-Shock Proteins - genetics ; Heat-Shock Proteins - metabolism ; Humans ; Hydrochloric acid ; Hydrogen ions ; Hydrogen-Ion Concentration ; Hypoxia ; Immunoenzyme Techniques ; Kinases ; Lactic acid ; Laser Capture Microdissection ; Markers ; Materials science ; Medicine and Health Sciences ; Microvasculature ; Mouth Neoplasms - drug therapy ; Mouth Neoplasms - metabolism ; Mouth Neoplasms - pathology ; Oral carcinoma ; Oral squamous cell carcinoma ; Otolaryngology ; pH effects ; Protein folding ; Proteins ; Reagents ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; RNA, Messenger - genetics ; Sensors ; Skin ; Squamous cell carcinoma ; Stress ; Stresses ; Studies ; Transcription factors ; Tumor cells ; Tumors ; Unfolded Protein Response - drug effects</subject><ispartof>PloS one, 2014-06, Vol.9 (6), p.e101053</ispartof><rights>COPYRIGHT 2014 Public Library of Science</rights><rights>2014 Visioli 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 Visioli et al 2014 Visioli et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c659t-3fe4cc144cddc6b5915313995b302d797191ef97505519655080688e4adea3123</citedby><cites>FETCH-LOGICAL-c659t-3fe4cc144cddc6b5915313995b302d797191ef97505519655080688e4adea3123</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/PMC4071032/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4071032/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24964091$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Visioli, Fernanda</creatorcontrib><creatorcontrib>Wang, Yugang</creatorcontrib><creatorcontrib>Alam, Goleeta N</creatorcontrib><creatorcontrib>Ning, Yu</creatorcontrib><creatorcontrib>Rados, Pantelis V</creatorcontrib><creatorcontrib>Nör, Jacques E</creatorcontrib><creatorcontrib>Polverini, Peter J</creatorcontrib><title>Glucose-regulated protein 78 (Grp78) confers chemoresistance to tumor endothelial cells under acidic stress</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>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.
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 anti-angiogenic drug Sunitinib was assessed with SRB assay.
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.
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.</description><subject>Acid resistance</subject><subject>Acidosis</subject><subject>Acidosis - drug therapy</subject><subject>Acidosis - metabolism</subject><subject>Acidosis - pathology</subject><subject>Acids</subject><subject>Analysis</subject><subject>Angiogenesis</subject><subject>Angiogenesis Inhibitors - pharmacology</subject><subject>Apoptosis</subject><subject>B cells</subject><subject>Biology and Life Sciences</subject><subject>Blotting, Western</subject><subject>Cancer</subject><subject>Cancer therapies</subject><subject>Carcinoma, Squamous Cell - drug therapy</subject><subject>Carcinoma, Squamous Cell - metabolism</subject><subject>Carcinoma, Squamous Cell - pathology</subject><subject>Cell Cycle</subject><subject>Cell death</subject><subject>Cell Proliferation</subject><subject>Cells, Cultured</subject><subject>Chemoresistance</subject><subject>Chemotherapy</subject><subject>Conditioning</subject><subject>Cytotoxicity</subject><subject>Dental materials</subject><subject>Dentistry</subject><subject>Dermis - drug effects</subject><subject>Dermis - metabolism</subject><subject>Dermis - pathology</subject><subject>Drug resistance</subject><subject>Drug Resistance, Neoplasm</subject><subject>Endoplasmic reticulum</subject><subject>Endoplasmic Reticulum Chaperone BiP</subject><subject>Endothelial cells</subject><subject>Endothelium</subject><subject>Endothelium, Vascular - drug effects</subject><subject>Endothelium, Vascular - metabolism</subject><subject>Endothelium, Vascular - pathology</subject><subject>Fluorescent Antibody Technique</subject><subject>Glucose</subject><subject>Glycoproteins</subject><subject>Head & neck cancer</subject><subject>Heat-Shock Proteins - genetics</subject><subject>Heat-Shock Proteins - metabolism</subject><subject>Humans</subject><subject>Hydrochloric acid</subject><subject>Hydrogen ions</subject><subject>Hydrogen-Ion Concentration</subject><subject>Hypoxia</subject><subject>Immunoenzyme Techniques</subject><subject>Kinases</subject><subject>Lactic acid</subject><subject>Laser Capture Microdissection</subject><subject>Markers</subject><subject>Materials science</subject><subject>Medicine and Health Sciences</subject><subject>Microvasculature</subject><subject>Mouth Neoplasms - drug therapy</subject><subject>Mouth Neoplasms - metabolism</subject><subject>Mouth Neoplasms - pathology</subject><subject>Oral carcinoma</subject><subject>Oral squamous cell carcinoma</subject><subject>Otolaryngology</subject><subject>pH effects</subject><subject>Protein folding</subject><subject>Proteins</subject><subject>Reagents</subject><subject>Real-Time Polymerase Chain Reaction</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>RNA, Messenger - genetics</subject><subject>Sensors</subject><subject>Skin</subject><subject>Squamous cell carcinoma</subject><subject>Stress</subject><subject>Stresses</subject><subject>Studies</subject><subject>Transcription factors</subject><subject>Tumor cells</subject><subject>Tumors</subject><subject>Unfolded Protein Response - drug effects</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>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNptUstuEzEUHSEQLYE_QGCJTVkk2OPHjDdIVVVCpUpsYG059p3EwbGD7UHi7-s006pBlRe27j3n3IdP07wneEFoR75s45iC9ot9DLDApB5OXzTnRNJ2LlpMXz55nzVvct7iiuiFeN2ctUwKhiU5b34v_WhihnmC9eh1AYv2KRZwAXU9ulimfdd_RiaGAVJGZgO7mCC7XHQwgEpEZawRBMHGsgHvtEcGvM9oDBYS0sZZZ1AulZTfNq8G7TO8m-5Z8-vb9c-r7_PbH8ubq8vbuRFcljkdgBlDGDPWGrHiknBKqJR8RXFrO9kRSWCQHcecEyk4xz0WfQ9MW9CUtHTWfDzq7n3MatpTVoQzzLqapxVxc0TYqLdqn9xOp38qaqfuAzGtlU7FGQ-KctPjbqX7DgzDlGiBB9OvTCsNJkzoqvV1qjaudmANhJK0PxE9zQS3Uev4VzHcEUwP7V5MAin-GSEXtXP5sEQdII73fRNaeyCiQj_9B31-ugm11nUAF4ZY65qDqLpkpOsZa6sTZs3iGVQ9FnaufjgMrsZPCOxIMCnmnGB4nJFgdbDkQzPqYEk1WbLSPjzdzyPpwYP0DmOU3PI</recordid><startdate>20140625</startdate><enddate>20140625</enddate><creator>Visioli, Fernanda</creator><creator>Wang, Yugang</creator><creator>Alam, Goleeta N</creator><creator>Ning, Yu</creator><creator>Rados, Pantelis V</creator><creator>Nör, Jacques E</creator><creator>Polverini, Peter J</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>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>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20140625</creationdate><title>Glucose-regulated protein 78 (Grp78) confers chemoresistance to tumor endothelial cells under acidic stress</title><author>Visioli, Fernanda ; Wang, Yugang ; Alam, Goleeta N ; Ning, Yu ; Rados, Pantelis V ; Nör, Jacques E ; Polverini, Peter J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c659t-3fe4cc144cddc6b5915313995b302d797191ef97505519655080688e4adea3123</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Acid resistance</topic><topic>Acidosis</topic><topic>Acidosis - drug therapy</topic><topic>Acidosis - metabolism</topic><topic>Acidosis - pathology</topic><topic>Acids</topic><topic>Analysis</topic><topic>Angiogenesis</topic><topic>Angiogenesis Inhibitors - pharmacology</topic><topic>Apoptosis</topic><topic>B cells</topic><topic>Biology and Life Sciences</topic><topic>Blotting, Western</topic><topic>Cancer</topic><topic>Cancer therapies</topic><topic>Carcinoma, Squamous Cell - drug therapy</topic><topic>Carcinoma, Squamous Cell - metabolism</topic><topic>Carcinoma, Squamous Cell - pathology</topic><topic>Cell Cycle</topic><topic>Cell death</topic><topic>Cell Proliferation</topic><topic>Cells, Cultured</topic><topic>Chemoresistance</topic><topic>Chemotherapy</topic><topic>Conditioning</topic><topic>Cytotoxicity</topic><topic>Dental materials</topic><topic>Dentistry</topic><topic>Dermis - drug effects</topic><topic>Dermis - metabolism</topic><topic>Dermis - pathology</topic><topic>Drug resistance</topic><topic>Drug Resistance, Neoplasm</topic><topic>Endoplasmic reticulum</topic><topic>Endoplasmic Reticulum Chaperone BiP</topic><topic>Endothelial cells</topic><topic>Endothelium</topic><topic>Endothelium, Vascular - drug effects</topic><topic>Endothelium, Vascular - metabolism</topic><topic>Endothelium, Vascular - pathology</topic><topic>Fluorescent Antibody Technique</topic><topic>Glucose</topic><topic>Glycoproteins</topic><topic>Head & neck cancer</topic><topic>Heat-Shock Proteins - genetics</topic><topic>Heat-Shock Proteins - metabolism</topic><topic>Humans</topic><topic>Hydrochloric acid</topic><topic>Hydrogen ions</topic><topic>Hydrogen-Ion Concentration</topic><topic>Hypoxia</topic><topic>Immunoenzyme Techniques</topic><topic>Kinases</topic><topic>Lactic acid</topic><topic>Laser Capture Microdissection</topic><topic>Markers</topic><topic>Materials science</topic><topic>Medicine and Health Sciences</topic><topic>Microvasculature</topic><topic>Mouth Neoplasms - drug therapy</topic><topic>Mouth Neoplasms - metabolism</topic><topic>Mouth Neoplasms - pathology</topic><topic>Oral carcinoma</topic><topic>Oral squamous cell carcinoma</topic><topic>Otolaryngology</topic><topic>pH effects</topic><topic>Protein folding</topic><topic>Proteins</topic><topic>Reagents</topic><topic>Real-Time Polymerase Chain Reaction</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>RNA, Messenger - genetics</topic><topic>Sensors</topic><topic>Skin</topic><topic>Squamous cell carcinoma</topic><topic>Stress</topic><topic>Stresses</topic><topic>Studies</topic><topic>Transcription factors</topic><topic>Tumor cells</topic><topic>Tumors</topic><topic>Unfolded Protein Response - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Visioli, Fernanda</creatorcontrib><creatorcontrib>Wang, Yugang</creatorcontrib><creatorcontrib>Alam, Goleeta N</creatorcontrib><creatorcontrib>Ning, Yu</creatorcontrib><creatorcontrib>Rados, Pantelis V</creatorcontrib><creatorcontrib>Nör, Jacques E</creatorcontrib><creatorcontrib>Polverini, Peter J</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</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 One Sustainability</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>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>Visioli, Fernanda</au><au>Wang, Yugang</au><au>Alam, Goleeta N</au><au>Ning, Yu</au><au>Rados, Pantelis V</au><au>Nör, Jacques E</au><au>Polverini, Peter J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Glucose-regulated protein 78 (Grp78) confers chemoresistance to tumor endothelial cells under acidic stress</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2014-06-25</date><risdate>2014</risdate><volume>9</volume><issue>6</issue><spage>e101053</spage><pages>e101053-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>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.
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 anti-angiogenic drug Sunitinib was assessed with SRB assay.
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.
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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24964091</pmid><doi>10.1371/journal.pone.0101053</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2014-06, Vol.9 (6), p.e101053 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1540471233 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Acid resistance Acidosis Acidosis - drug therapy Acidosis - metabolism Acidosis - pathology Acids Analysis Angiogenesis Angiogenesis Inhibitors - pharmacology Apoptosis B cells Biology and Life Sciences Blotting, Western Cancer Cancer therapies Carcinoma, Squamous Cell - drug therapy Carcinoma, Squamous Cell - metabolism Carcinoma, Squamous Cell - pathology Cell Cycle Cell death Cell Proliferation Cells, Cultured Chemoresistance Chemotherapy Conditioning Cytotoxicity Dental materials Dentistry Dermis - drug effects Dermis - metabolism Dermis - pathology Drug resistance Drug Resistance, Neoplasm Endoplasmic reticulum Endoplasmic Reticulum Chaperone BiP Endothelial cells Endothelium Endothelium, Vascular - drug effects Endothelium, Vascular - metabolism Endothelium, Vascular - pathology Fluorescent Antibody Technique Glucose Glycoproteins Head & neck cancer Heat-Shock Proteins - genetics Heat-Shock Proteins - metabolism Humans Hydrochloric acid Hydrogen ions Hydrogen-Ion Concentration Hypoxia Immunoenzyme Techniques Kinases Lactic acid Laser Capture Microdissection Markers Materials science Medicine and Health Sciences Microvasculature Mouth Neoplasms - drug therapy Mouth Neoplasms - metabolism Mouth Neoplasms - pathology Oral carcinoma Oral squamous cell carcinoma Otolaryngology pH effects Protein folding Proteins Reagents Real-Time Polymerase Chain Reaction Reverse Transcriptase Polymerase Chain Reaction RNA, Messenger - genetics Sensors Skin Squamous cell carcinoma Stress Stresses Studies Transcription factors Tumor cells Tumors Unfolded Protein Response - drug effects |
| title | Glucose-regulated protein 78 (Grp78) confers chemoresistance to tumor endothelial cells under acidic stress |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-03T03%3A08%3A27IST&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=Glucose-regulated%20protein%2078%20(Grp78)%20confers%20chemoresistance%20to%20tumor%20endothelial%20cells%20under%20acidic%20stress&rft.jtitle=PloS%20one&rft.au=Visioli,%20Fernanda&rft.date=2014-06-25&rft.volume=9&rft.issue=6&rft.spage=e101053&rft.pages=e101053-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0101053&rft_dat=%3Cgale_plos_%3EA417844205%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=1540471233&rft_id=info:pmid/24964091&rft_galeid=A417844205&rft_doaj_id=oai_doaj_org_article_35c807ba87ec4031a60fc8bc29c0146a&rfr_iscdi=true |