Autophagy inhibition facilitates erlotinib cytotoxicity in lung cancer cells through modulation of endoplasmic reticulum stress.
Identifieur interne : 000211 ( PubMed/Corpus ); précédent : 000210; suivant : 000212Autophagy inhibition facilitates erlotinib cytotoxicity in lung cancer cells through modulation of endoplasmic reticulum stress.
Auteurs : Zhongliang Wang ; Tingting Du ; Xiaorong Dong ; Zhenyu Li ; Gang Wu ; Ruiguang ZhangSource :
- International journal of oncology [ 1791-2423 ] ; 2016.
English descriptors
- KwdEn :
- Antineoplastic Agents (pharmacology), Autophagy (drug effects), Carcinoma, Non-Small-Cell Lung (drug therapy), Carcinoma, Non-Small-Cell Lung (metabolism), Cell Line, Tumor, Cell Proliferation (drug effects), Cell Survival (drug effects), Chloroquine (pharmacology), Drug Resistance, Neoplasm (drug effects), Drug Synergism, Endoplasmic Reticulum Stress (drug effects), ErbB Receptors (antagonists & inhibitors), Erlotinib Hydrochloride (pharmacology), Humans, Lung Neoplasms (drug therapy), Lung Neoplasms (metabolism), Protein Kinase Inhibitors (pharmacology), RNA, Small Interfering (pharmacology), Transcription Factor CHOP (genetics).
- MESH :
- chemical , antagonists & inhibitors : ErbB Receptors.
- chemical , genetics : Transcription Factor CHOP.
- chemical , pharmacology : Antineoplastic Agents, Chloroquine, Erlotinib Hydrochloride, Protein Kinase Inhibitors, RNA, Small Interfering.
- drug effects : Autophagy, Cell Proliferation, Cell Survival, Drug Resistance, Neoplasm, Endoplasmic Reticulum Stress.
- drug therapy : Carcinoma, Non-Small-Cell Lung, Lung Neoplasms.
- metabolism : Carcinoma, Non-Small-Cell Lung, Lung Neoplasms.
- Cell Line, Tumor, Drug Synergism, Humans.
Abstract
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have revolutionized the treatment for non-small cell lung cancer patients, but acquired resistance limit the efficiency of this treatment. As a homeostatic cellular recycling mechanism, autophagy has been proposed to participate in the EGFR-TKI resistance. However, the role of autophagy in lung cancer treatment and the underlying mechanisms have not been clarified. In this study, we found the sensitivity to erlotinib, a well-used EGFR-TKI, was correlated with basal autophagy level. Erlotinib was able to induce autophagy not only in TKI-sensitive, but also TKI-resistant cancer cells. Inhibition of autophagy significantly enhanced cytotoxicity of erlotinib in TKI-resistant cancer cells via modulation of endoplasmic reticulum (ER) stress induced apoptosis. In this process, CCAAT/enhancer binding protein homologous protein (CHOP) acted as an executioner. Downregulation of CHOP with siRNA blocked the autophagy inhibition and erlotinib co-treatment induced apoptosis and prevented cancer cells from this co-treatment-induced cell death. Our findings suggest that autophagy inhibition overcomes erlotinib resistance through modulation of ER stress mediated apoptosis.
DOI: 10.3892/ijo.2016.3468
PubMed: 27035631
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pubmed:27035631Le document en format XML
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China.</nlm:affiliation></affiliation></author><author><name sortKey="Dong, Xiaorong" sort="Dong, Xiaorong" uniqKey="Dong X" first="Xiaorong" last="Dong">Xiaorong Dong</name><affiliation><nlm:affiliation>Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China.</nlm:affiliation></affiliation></author><author><name sortKey="Li, Zhenyu" sort="Li, Zhenyu" uniqKey="Li Z" first="Zhenyu" last="Li">Zhenyu Li</name><affiliation><nlm:affiliation>Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China.</nlm:affiliation></affiliation></author><author><name sortKey="Wu, Gang" sort="Wu, Gang" uniqKey="Wu G" first="Gang" last="Wu">Gang Wu</name><affiliation><nlm:affiliation>Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China.</nlm:affiliation></affiliation></author><author><name sortKey="Zhang, Ruiguang" sort="Zhang, Ruiguang" uniqKey="Zhang R" first="Ruiguang" last="Zhang">Ruiguang Zhang</name><affiliation><nlm:affiliation>Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China.</nlm:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2016">2016</date><idno type="RBID">pubmed:27035631</idno><idno type="pmid">27035631</idno><idno type="doi">10.3892/ijo.2016.3468</idno><idno type="wicri:Area/PubMed/Corpus">000211</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000211</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Autophagy inhibition facilitates erlotinib cytotoxicity in lung cancer cells through modulation of endoplasmic reticulum stress.</title><author><name sortKey="Wang, Zhongliang" sort="Wang, Zhongliang" uniqKey="Wang Z" first="Zhongliang" last="Wang">Zhongliang Wang</name><affiliation><nlm:affiliation>Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China.</nlm:affiliation></affiliation></author><author><name sortKey="Du, Tingting" sort="Du, Tingting" uniqKey="Du T" first="Tingting" last="Du">Tingting Du</name><affiliation><nlm:affiliation>Department of Endocrinology, Wuhan Medical and Health Center for Women and Children, Wuhan, Hubei, P.R. China.</nlm:affiliation></affiliation></author><author><name sortKey="Dong, Xiaorong" sort="Dong, Xiaorong" uniqKey="Dong X" first="Xiaorong" last="Dong">Xiaorong Dong</name><affiliation><nlm:affiliation>Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China.</nlm:affiliation></affiliation></author><author><name sortKey="Li, Zhenyu" sort="Li, Zhenyu" uniqKey="Li Z" first="Zhenyu" last="Li">Zhenyu Li</name><affiliation><nlm:affiliation>Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China.</nlm:affiliation></affiliation></author><author><name sortKey="Wu, Gang" sort="Wu, Gang" uniqKey="Wu G" first="Gang" last="Wu">Gang Wu</name><affiliation><nlm:affiliation>Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China.</nlm:affiliation></affiliation></author><author><name sortKey="Zhang, Ruiguang" sort="Zhang, Ruiguang" uniqKey="Zhang R" first="Ruiguang" last="Zhang">Ruiguang Zhang</name><affiliation><nlm:affiliation>Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China.</nlm:affiliation></affiliation></author></analytic><series><title level="j">International journal of oncology</title><idno type="eISSN">1791-2423</idno><imprint><date when="2016" type="published">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antineoplastic Agents (pharmacology)</term><term>Autophagy (drug effects)</term><term>Carcinoma, Non-Small-Cell Lung (drug therapy)</term><term>Carcinoma, Non-Small-Cell Lung (metabolism)</term><term>Cell Line, Tumor</term><term>Cell Proliferation (drug effects)</term><term>Cell Survival (drug effects)</term><term>Chloroquine (pharmacology)</term><term>Drug Resistance, Neoplasm (drug effects)</term><term>Drug Synergism</term><term>Endoplasmic Reticulum Stress (drug effects)</term><term>ErbB Receptors (antagonists & inhibitors)</term><term>Erlotinib Hydrochloride (pharmacology)</term><term>Humans</term><term>Lung Neoplasms (drug therapy)</term><term>Lung Neoplasms (metabolism)</term><term>Protein Kinase Inhibitors (pharmacology)</term><term>RNA, Small Interfering (pharmacology)</term><term>Transcription Factor CHOP (genetics)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>ErbB Receptors</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Transcription Factor CHOP</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antineoplastic Agents</term><term>Chloroquine</term><term>Erlotinib Hydrochloride</term><term>Protein Kinase Inhibitors</term><term>RNA, Small Interfering</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Autophagy</term><term>Cell Proliferation</term><term>Cell Survival</term><term>Drug Resistance, Neoplasm</term><term>Endoplasmic Reticulum Stress</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Carcinoma, Non-Small-Cell Lung</term><term>Lung Neoplasms</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Carcinoma, Non-Small-Cell Lung</term><term>Lung Neoplasms</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Cell Line, Tumor</term><term>Drug Synergism</term><term>Humans</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have revolutionized the treatment for non-small cell lung cancer patients, but acquired resistance limit the efficiency of this treatment. As a homeostatic cellular recycling mechanism, autophagy has been proposed to participate in the EGFR-TKI resistance. However, the role of autophagy in lung cancer treatment and the underlying mechanisms have not been clarified. In this study, we found the sensitivity to erlotinib, a well-used EGFR-TKI, was correlated with basal autophagy level. Erlotinib was able to induce autophagy not only in TKI-sensitive, but also TKI-resistant cancer cells. Inhibition of autophagy significantly enhanced cytotoxicity of erlotinib in TKI-resistant cancer cells via modulation of endoplasmic reticulum (ER) stress induced apoptosis. In this process, CCAAT/enhancer binding protein homologous protein (CHOP) acted as an executioner. Downregulation of CHOP with siRNA blocked the autophagy inhibition and erlotinib co-treatment induced apoptosis and prevented cancer cells from this co-treatment-induced cell death. Our findings suggest that autophagy inhibition overcomes erlotinib resistance through modulation of ER stress mediated apoptosis. </div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">27035631</PMID><DateCompleted><Year>2017</Year><Month>03</Month><Day>10</Day></DateCompleted><DateRevised><Year>2018</Year><Month>12</Month><Day>02</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1791-2423</ISSN><JournalIssue CitedMedium="Internet"><Volume>48</Volume><Issue>6</Issue><PubDate><Year>2016</Year><Month>Jun</Month></PubDate></JournalIssue><Title>International journal of oncology</Title><ISOAbbreviation>Int. J. Oncol.</ISOAbbreviation></Journal><ArticleTitle>Autophagy inhibition facilitates erlotinib cytotoxicity in lung cancer cells through modulation of endoplasmic reticulum stress.</ArticleTitle><Pagination><MedlinePgn>2558-66</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.3892/ijo.2016.3468</ELocationID><Abstract><AbstractText>Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have revolutionized the treatment for non-small cell lung cancer patients, but acquired resistance limit the efficiency of this treatment. As a homeostatic cellular recycling mechanism, autophagy has been proposed to participate in the EGFR-TKI resistance. However, the role of autophagy in lung cancer treatment and the underlying mechanisms have not been clarified. In this study, we found the sensitivity to erlotinib, a well-used EGFR-TKI, was correlated with basal autophagy level. Erlotinib was able to induce autophagy not only in TKI-sensitive, but also TKI-resistant cancer cells. Inhibition of autophagy significantly enhanced cytotoxicity of erlotinib in TKI-resistant cancer cells via modulation of endoplasmic reticulum (ER) stress induced apoptosis. In this process, CCAAT/enhancer binding protein homologous protein (CHOP) acted as an executioner. Downregulation of CHOP with siRNA blocked the autophagy inhibition and erlotinib co-treatment induced apoptosis and prevented cancer cells from this co-treatment-induced cell death. Our findings suggest that autophagy inhibition overcomes erlotinib resistance through modulation of ER stress mediated apoptosis. </AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Wang</LastName><ForeName>Zhongliang</ForeName><Initials>Z</Initials><AffiliationInfo><Affiliation>Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Du</LastName><ForeName>Tingting</ForeName><Initials>T</Initials><AffiliationInfo><Affiliation>Department of Endocrinology, Wuhan Medical and Health Center for Women and Children, Wuhan, Hubei, P.R. China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Dong</LastName><ForeName>Xiaorong</ForeName><Initials>X</Initials><AffiliationInfo><Affiliation>Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Li</LastName><ForeName>Zhenyu</ForeName><Initials>Z</Initials><AffiliationInfo><Affiliation>Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Wu</LastName><ForeName>Gang</ForeName><Initials>G</Initials><AffiliationInfo><Affiliation>Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Zhang</LastName><ForeName>Ruiguang</ForeName><Initials>R</Initials><AffiliationInfo><Affiliation>Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2016</Year><Month>04</Month><Day>01</Day></ArticleDate></Article><MedlineJournalInfo><Country>Greece</Country><MedlineTA>Int J Oncol</MedlineTA><NlmUniqueID>9306042</NlmUniqueID><ISSNLinking>1019-6439</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000970">Antineoplastic Agents</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C497249">DDIT3 protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D047428">Protein Kinase Inhibitors</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D034741">RNA, Small 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MajorTopicYN="N">Drug Resistance, Neoplasm</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="Y">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D004357" MajorTopicYN="N">Drug Synergism</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D059865" MajorTopicYN="N">Endoplasmic Reticulum Stress</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="Y">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D066246" MajorTopicYN="N">ErbB Receptors</DescriptorName><QualifierName UI="Q000037" MajorTopicYN="N">antagonists & inhibitors</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000069347" MajorTopicYN="N">Erlotinib Hydrochloride</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008175" MajorTopicYN="N">Lung Neoplasms</DescriptorName><QualifierName UI="Q000188" MajorTopicYN="N">drug therapy</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D047428" MajorTopicYN="N">Protein Kinase Inhibitors</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D034741" MajorTopicYN="N">RNA, Small Interfering</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D051742" MajorTopicYN="N">Transcription Factor CHOP</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2016</Year><Month>01</Month><Day>27</Day></PubMedPubDate><PubMedPubDate 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