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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
24
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pubmed:dateCreated |
2010-12-16
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pubmed:abstractText |
The molecular mechanism by which epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) induce apoptosis in non-small cell-lung cancer (NSCLC) cells that are positive for activating mutations of the EGFR remains unclear. In this study, we report the effects of the EGFR-TKI gefitinib on expression of the antiapoptotic protein survivin that have functional consequences in EGFR mutation-positive NSCLC cells. Immunoblot analysis revealed that gefitinib downregulated survivin expression, likely through inhibition of the PI3K-AKT signaling pathway, in NSCLC cells positive for EGFR mutation. Stable overexpression of survivin attenuated gefitinib-induced apoptosis and also inhibited the antitumor effect of gefitinib in human tumor xenografts. Furthermore, the combination of survivin overexpression with inhibition of the gefitinib-induced upregulation of the proapoptotic protein BIM attenuated gefitinib-induced apoptosis to a greater extent than either approach alone. Our results indicate that downregulation of survivin plays a pivotal role in gefitinib-induced apoptosis in EGFR mutation-positive NSCLC cells. Furthermore, they suggest that simultaneous interruption of the PI3K-AKT-survivin and MEK-ERK-BIM signaling pathways is responsible for EGFR-TKI-induced apoptotic death in these cells.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Apoptosis Regulatory Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/BIRC5 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Bcl-2-like protein 11,
http://linkedlifedata.com/resource/pubmed/chemical/Inhibitor of Apoptosis Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Membrane Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Microtubule-Associated Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Oncogene Protein v-akt,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphatidylinositol 3-Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Quinazolines,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger,
http://linkedlifedata.com/resource/pubmed/chemical/Receptor, Epidermal Growth Factor,
http://linkedlifedata.com/resource/pubmed/chemical/gefitinib
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pubmed:status |
MEDLINE
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pubmed:month |
Dec
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pubmed:issn |
1538-7445
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pubmed:author |
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pubmed:copyrightInfo |
©2010 AACR.
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pubmed:issnType |
Electronic
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pubmed:day |
15
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pubmed:volume |
70
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
10402-10
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pubmed:dateRevised |
2011-11-17
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pubmed:meshHeading |
pubmed-meshheading:21159653-Apoptosis,
pubmed-meshheading:21159653-Apoptosis Regulatory Proteins,
pubmed-meshheading:21159653-Carcinoma, Non-Small-Cell Lung,
pubmed-meshheading:21159653-Cell Line, Tumor,
pubmed-meshheading:21159653-Down-Regulation,
pubmed-meshheading:21159653-Gene Knockdown Techniques,
pubmed-meshheading:21159653-Genes, erbB-1,
pubmed-meshheading:21159653-Humans,
pubmed-meshheading:21159653-Inhibitor of Apoptosis Proteins,
pubmed-meshheading:21159653-Lung Neoplasms,
pubmed-meshheading:21159653-Membrane Proteins,
pubmed-meshheading:21159653-Microtubule-Associated Proteins,
pubmed-meshheading:21159653-Mutation,
pubmed-meshheading:21159653-Oncogene Protein v-akt,
pubmed-meshheading:21159653-Phosphatidylinositol 3-Kinases,
pubmed-meshheading:21159653-Proto-Oncogene Proteins,
pubmed-meshheading:21159653-Quinazolines,
pubmed-meshheading:21159653-RNA, Messenger,
pubmed-meshheading:21159653-Receptor, Epidermal Growth Factor
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pubmed:year |
2010
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pubmed:articleTitle |
Role of survivin in EGFR inhibitor-induced apoptosis in non-small cell lung cancers positive for EGFR mutations.
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pubmed:affiliation |
Department of Medical Oncology, Kinki University School of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka, Japan.
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pubmed:publicationType |
Journal Article
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