Cytosolic PKM2 stabilizes mutant EGFR protein expression through regulating HSP90-EGFR association.
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.
Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Y-C
YC
Yang
Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan.
T-Y
TY
Cheng
Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
S-M
SM
Huang
Genomics Research Center, Academia Sinica, Taipei, Taiwan.
C-Y
CY
Su
Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.
P-W
PW
Yang
Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.
J-M
JM
Lee
Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.|Genomics Research Center, Academia Sinica, Taipei, Taiwan.
C-K
CK
Chen
Genomics Research Center, Academia Sinica, Taipei, Taiwan.
M
M
Hsiao
Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
K-T
KT
Hua
Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.|Institute of Biochemical Sciences, College of Life Science Sciences, National Taiwan University, Taipei, Taiwan.
M-L
ML
Kuo
D000072283:A549 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D003600:Cytosol / Q000201:enzymology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009154:Mutation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D055550:Protein Stability; D011770:Pyruvate Kinase / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D047428:Protein Kinase Inhibitors; D011770:Pyruvate Kinase; C512478:EGFR protein, human; D066246:ErbB Receptors