Role of Survivin in EGFR Inhibitor–Induced Apoptosis in Non–Small Cell Lung Cancers Positive for EGFR Mutations

Cancer Research - Tập 70 Số 24 - Trang 10402-10410 - 2010
Kunio Okamoto1, Isamu Okamoto1, Wataru Okamoto1, Kaoru Tanaka1, Ken Takezawa1, Kiyoko Kuwata1, Haruka Yamaguchi1, Kazuto Nishio1, Kazuhiko Nakagawa1
1Authors' Affiliations: Departments of 1Medical Oncology and 2Genome Biology, Kinki University School of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka, Japan

Tóm tắt

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. Cancer Res; 70(24); 10402–10. ©2010 AACR.

Từ khóa


Tài liệu tham khảo

Blanc-Brude, 2003, Therapeutic targeting of the survivin pathway in cancer: initiation of mitochondrial apoptosis and suppression of tumor-associated angiogenesis, Clin Cancer Res, 9, 2683

Dohi, 2004, An IAP-IAP complex inhibits apoptosis, J Biol Chem, 279, 34087, 10.1074/jbc.C400236200

Li, 1998, Control of apoptosis and mitotic spindle checkpoint by survivin, Nature, 396, 580, 10.1038/25141

Ambrosini, 1997, A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma, Nat Med, 3, 917, 10.1038/nm0897-917

Ambrosini, 1998, Induction of apoptosis and inhibition of cell proliferation by survivin gene targeting, J Biol Chem, 273, 11177, 10.1074/jbc.273.18.11177

Kallio, 2001, Human inhibitor of apoptosis protein (IAP) survivin participates in regulation of chromosome segregation and mitotic exit, FASEB J, 15, 2721, 10.1096/fj.01-0280fje

Li, 1999, The cancer antiapoptosis mouse survivin gene: characterization of locus and transcriptional requirements of basal and cell cycle-dependent expression, Cancer Res, 59, 3143

Carter, 2001, Cytokine-regulated expression of survivin in myeloid leukemia, Blood, 97, 2784, 10.1182/blood.V97.9.2784

Fang, 2009, Transcriptional regulation of survivin by c-Myc in BCR/ABL-transformed cells: implications in anti-leukaemic strategy, J Cell Mol Med, 13, 2039, 10.1111/j.1582-4934.2008.00549.x

Beierle, 2005, VEGF-mediated survivin expression in neuroblastoma cells, J Surg Res, 127, 21, 10.1016/j.jss.2005.03.009

Tran, 2002, A role for survivin in chemoresistance of endothelial cells mediated by VEGF, Proc Natl Acad Sci U S A, 99, 4349, 10.1073/pnas.072586399

Fan, 2008, The role of survivin on overall survival of non-small cell lung cancer, a meta-analysis of published literatures, Lung Cancer, 61, 91, 10.1016/j.lungcan.2007.11.011

Huang, 2007, E2F1 overexpression correlates with thymidylate synthase and survivin gene expressions and tumor proliferation in non small-cell lung cancer, Clin Cancer Res, 13, 6938, 10.1158/1078-0432.CCR-07-1539

Krepela, 2009, Increased expression of inhibitor of apoptosis proteins, survivin and XIAP, in non-small cell lung carcinoma, Int J Oncol, 35, 1449, 10.3892/ijo_00000464

Mendelsohn, 2000, The EGF receptor family as targets for cancer therapy, Oncogene, 19, 6550, 10.1038/sj.onc.1204082

Schlessinger, 2000, Cell signaling by receptor tyrosine kinases, Cell, 103, 211, 10.1016/S0092-8674(00)00114-8

Hynes, 2005, ERBB receptors and cancer: the complexity of targeted inhibitors, Nat Rev Cancer, 5, 341, 10.1038/nrc1609

Paez, 2004, EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy, Science, 304, 1497, 10.1126/science.1099314

Shepherd, 2005, Erlotinib in previously treated non-small-cell lung cancer, N Engl J Med, 353, 123, 10.1056/NEJMoa050753

Sordella, 2004, Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways, Science, 305, 1163, 10.1126/science.1101637

Tracy, 2004, Gefitinib induces apoptosis in the EGFRL858R non-small-cell lung cancer cell line H3255, Cancer Res, 64, 7241, 10.1158/0008-5472.CAN-04-1905

Ling, 2008, Erlotinib induces mitochondrial-mediated apoptosis in human H3255 non-small-cell lung cancer cells with epidermal growth factor receptorL858R mutation through mitochondrial oxidative phosphorylation-dependent activation of BAX and BAK, Mol Pharmacol, 74, 793, 10.1124/mol.107.044396

Koizumi, 2005, Establishment of a human non-small cell lung cancer cell line resistant to gefitinib, Int J Cancer, 116, 36, 10.1002/ijc.20985

Tanaka, 2009, SRPX2 is overexpressed in gastric cancer and promotes cellular migration and adhesion, Int J Cancer, 124, 1072, 10.1002/ijc.24065

Costa, 2007, BIM mediates EGFR tyrosine kinase inhibitor-induced apoptosis in lung cancers with oncogenic EGFR mutations, PLoS Med, 4, 1669, 10.1371/journal.pmed.0040315

Cragg, 2007, Gefitinib-induced killing of NSCLC cell lines expressing mutant EGFR requires BIM and can be enhanced by BH3 mimetics, PLoS Med, 4, 1681, 10.1371/journal.pmed.0040316

Gong, 2007, Induction of BIM is essential for apoptosis triggered by EGFR kinase inhibitors in mutant EGFR-dependent lung adenocarcinomas, PLoS Med, 4, 1655, 10.1371/journal.pmed.0040294

Asanuma, 2005, Survivin expression is regulated by coexpression of human epidermal growth factor receptor 2 and epidermal growth factor receptor via phosphatidylinositol 3-kinase/AKT signaling pathway in breast cancer cells, Cancer Res, 65, 11018, 10.1158/0008-5472.CAN-05-0491

Xia, 2006, Regulation of survivin by ErbB2 signaling: therapeutic implications for ErbB2-overexpressing breast cancers, Cancer Res, 66, 1640, 10.1158/0008-5472.CAN-05-2000

Zhao, 2010, Regulation of survivin by PI3K/Akt/p70S6K1 pathway, Biochem Biophys Res Commun, 395, 219, 10.1016/j.bbrc.2010.03.165

Faber, 2009, Differential induction of apoptosis in HER2 and EGFR addicted cancers following PI3K inhibition, Proc Natl Acad Sci U S A, 106, 19503, 10.1073/pnas.0905056106

Sos, 2009, PTEN loss contributes to erlotinib resistance in EGFR-mutant lung cancer by activation of Akt and EGFR, Cancer Res, 69, 3256, 10.1158/0008-5472.CAN-08-4055

Okamoto, 2009, Epidermal growth factor receptor in relation to tumor development: EGFR-targeted anticancer therapy, FEBS J, 277, 309, 10.1111/j.1742-4658.2009.07449.x

Engelman, 2007, MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling, Science, 316, 1039, 10.1126/science.1141478

Ercan, 2010, Amplification of EGFR T790M causes resistance to an irreversible EGFR inhibitor, Oncogene, 29, 2346, 10.1038/onc.2009.526

Pao, 2005, Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain, PLoS Med, 2, 225

Yano, 2008, Hepatocyte growth factor induces gefitinib resistance of lung adenocarcinoma with epidermal growth factor receptor-activating mutations, Cancer Res, 68, 9479, 10.1158/0008-5472.CAN-08-1643

Takeda, 2010, De novo resistance to epidermal growth factor receptor-tyrosine kinase inhibitors in EGFR mutation-positive patients with non-small cell lung cancer, J Thorac Oncol, 5, 399, 10.1097/JTO.0b013e3181cee47e

Thông tin
Thông tin xuất bản

Cancer Research

Tập 70 Số 24

10402-10410

Thông tin tác giả