title: Role of survivin in EGFR inhibitor-induced apoptosis in non-small cell lung cancers positive for EGFR mutations.
abstract: 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.
authors.affiliation: Department of Medical Oncology, Kinki University School of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka, Japan.
authors.forename: Kunio
authors.initials: K
authors.lastname: Okamoto
authors.forename: Isamu
authors.initials: I
authors.lastname: Okamoto
authors.forename: Wataru
authors.initials: W
authors.lastname: Okamoto
authors.forename: Kaoru
authors.initials: K
authors.lastname: Tanaka
authors.forename: Ken
authors.initials: K
authors.lastname: Takezawa
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Kuwata
authors.forename: Haruka
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nishio
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakagawa
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics; D000072224:Bcl-2-Like Protein 11; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000077156:Gefitinib; D055785:Gene Knockdown Techniques; D018773:Genes, erbB-1; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis* / Q000235:genetics; D009154:Mutation; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D011799:Quinazolines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D000077022:Survivin
chemical_list: D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D066246:ErbB Receptors; D000077156:Gefitinib; D051034:Inhibitor of Apoptosis Proteins; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D012333:RNA, Messenger; D000077022:Survivin; C000606775:BCL2L11 protein, human; C107489:BIRC5 protein, human