https://scholars.lib.ntu.edu.tw/handle/123456789/481556
標題: | Cytosolic PKM2 stabilizes mutant EGFR protein expression through regulating HSP90-EGFR association | 作者: | Yang Y.-C. TSU-YAO CHENG Huang S.-M. Su C.-Y. Yang P.-W. JANG-MING LEE Chen C.-K. Hsiao M. KUO-TAI HUA Kuo M.-L. |
公開日期: | 2016 | 出版社: | Nature Publishing Group | 卷: | 35 | 期: | 26 | 起(迄)頁: | 3387-3398 | 來源出版物: | Oncogene | 摘要: | Secondary mutation of epidermal growth factor receptor (EGFR) resulting in drug resistance is one of the most critical issues in lung cancer therapy. Several drugs are being developed to overcome EGFR tyrosine kinase inhibitor (TKI) resistance. Here, we report that pyruvate kinase M2 (PKM2) stabilized mutant EGFR protein by direct interaction and sustained cell survival signaling in lung cancer cells. PKM2 silencing resulted in markedly reduced mutant EGFR expression in TKI-sensitive or -resistant human lung cancer cells, and in inhibition of tumor growth in their xenografts, concomitant with downregulation of EGFR-related signaling. Mechanistically, PKM2 directly interacted with mutant EGFR and heat-shock protein 90 (HSP90), and thus stabilized EGFR by maintaining its binding with HSP90 and co-chaperones. Stabilization of EGFR relied on dimeric PKM2, and the protein half-life of mutant EGFR decreased when PKM2 was forced into its tetramer form. Clinical levels of PKM2 positively correlated with mutant EGFR expression and with patient outcome. These results reveal a previously undescribed non-glycolysis function of PKM2 in the cytoplasm, which contribute to EGFR-dependent tumorigenesis and provide a novel strategy to overcome drug resistance to EGFR TKIs. ? 2016 Macmillan Publishers Limited All rights reserved. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-84976870085&doi=10.1038%2fonc.2015.397&partnerID=40&md5=dab00728998938e07184e66fd05bcdf4 https://scholars.lib.ntu.edu.tw/handle/123456789/481556 |
ISSN: | 0950-9232 | DOI: | 10.1038/onc.2015.397 | SDG/關鍵字: | chaperone; epidermal growth factor receptor; heat shock protein 90; mutant protein; pyruvate kinase; pyruvate kinase m2; unclassified drug; antineoplastic agent; EGFR protein, human; epidermal growth factor receptor; heat shock protein 90; protein binding; protein kinase inhibitor; pyruvate kinase; A549 cell line; apoptosis; Article; cell growth; cell proliferation; cell survival; cell viability; colony formation; controlled study; cytoplasm; cytosol; half life time; human; human cell; in vitro study; in vivo study; lung cancer cell line; non small cell lung cancer; priority journal; protein analysis; protein binding; protein degradation; protein expression; protein protein interaction; protein stability; signal transduction; tumor growth; tumor volume; xenograft; A-549 cell line; animal; antagonists and inhibitors; cytosol; drug effects; drug resistance; drug screening; enzymology; genetics; immunoblotting; knockout mouse; Lung Neoplasms; metabolism; mutation; nonobese diabetic mouse; reverse transcription polymerase chain reaction; RNA interference; SCID mouse; survival analysis; tumor cell line; A549 Cells; Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Cytosol; Drug Resistance, Neoplasm; HSP90 Heat-Shock Proteins; Humans; Immunoblotting; Lung Neoplasms; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Mutation; Protein Binding; Protein Kinase Inhibitors; Protein Stability; Pyruvate Kinase; Receptor, Epidermal Growth Factor; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Survival Analysis; Tumor Burden; Xenograft Model Antitumor Assays |
顯示於: | 醫學系 |
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