Cytosolic PKM2 stabilizes mutant EGFR protein expression through regulating HSP90–EGFR association
| Autor: | Chi Kuan Chen, Jang-Ming Lee, Michael Hsiao, Tsu-Yao Cheng, Kuo Tai Hua, Yi Chieh Yang, Huang Sm, Chia Yi Su, Pei Wen Yang, M L Kuo |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Cancer Research Lung Neoplasms Cell Survival Immunoblotting Pyruvate Kinase Mutant Antineoplastic Agents Mice SCID Biology PKM2 medicine.disease_cause 03 medical and health sciences Cytosol Growth factor receptor Mice Inbred NOD Cell Line Tumor medicine Genetics Animals Humans ERBB3 HSP90 Heat-Shock Proteins Epidermal growth factor receptor Protein Kinase Inhibitors Molecular Biology Mice Knockout Protein Stability Reverse Transcriptase Polymerase Chain Reaction Cell cycle Survival Analysis Xenograft Model Antitumor Assays Tumor Burden ErbB Receptors 030104 developmental biology A549 Cells Drug Resistance Neoplasm Mutation Immunology Cancer research biology.protein Cyclin-dependent kinase 8 RNA Interference Carcinogenesis Protein Binding |
| Zdroj: | Europe PubMed Central |
| ISSN: | 1476-5594 0950-9232 |
| DOI: | 10.1038/onc.2015.397 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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