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Cytosolic PKM2 stabilizes mutant EGFR protein expression through regulating HSP90–EGFR association
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Cytosolic PKM2 stabilizes mutant EGFR protein expression through regulating HSP90–EGFR association
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Journal Article
Cytosolic PKM2 stabilizes mutant EGFR protein expression through regulating HSP90–EGFR association
2016
Overview
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.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 13/51
/ 14
/ 14/19
/ 42
/ 42/109
/ 59
/ 59/5
/ 64
/ 64/60
/ 82
/ 82/80
/ 96
/ 96/2
/ Animals
/ Antineoplastic Agents - pharmacology
/ Cell Survival - drug effects
/ Cellular signal transduction
/ Drug Resistance, Neoplasm - drug effects
/ Drug Resistance, Neoplasm - genetics
/ Epidermal growth factor receptors
/ HSP90 Heat-Shock Proteins - metabolism
/ Humans
/ Kinases
/ Lung Neoplasms - drug therapy
/ Medicine
/ Mutants
/ Mutation
/ Oncology
/ Protein Kinase Inhibitors - pharmacology
/ Proteins
/ Pyruvate Kinase - metabolism
/ Receptor, Epidermal Growth Factor - antagonists & inhibitors
/ Receptor, Epidermal Growth Factor - genetics
/ Receptor, Epidermal Growth Factor - metabolism
/ Reverse Transcriptase Polymerase Chain Reaction
