Mitochondrial translocation of EGFR regulates mitochondria dynamics and promotes metastasis in NSCLC.
Dysfunction of the mitochondria is well-known for being associated with cancer progression. In the present study, we analyzed the mitochondria proteomics of lung cancer cell lines with different invasion abilities and found that EGFR is highly expressed in the mitochondria of highly invasive non-small-cell lung cancer (NSCLC) cells. EGF induces the mitochondrial translocation of EGFR; further, it leads to mitochondrial fission and redistribution in the lamellipodia, upregulates cellular ATP production, and enhances motility in vitro and in vivo. Moreover, EGFR can regulate mitochondrial dynamics by interacting with Mfn1 and disturbing Mfn1 polymerization. Overexpression of Mfn1 reverses the phenotypes resulting from EGFR mitochondrial translocation. We show that the mitochondrial EGFR expressions are higher in paired samples of the metastatic lymph node as compared with primary lung tumor and are inversely correlated with the overall survival in NSCLC patients. Therefore, our results demonstrate that besides the canonical role of EGFR as a receptor tyrosine, the mitochondrial translocation of EGFR may enhance cancer invasion and metastasis through regulating mitochondria dynamics.
Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
Ting-Fang
TF
Che
Institute of Biomedical Science, Academia Sinica, Taipei 115, Taiwan.
Ching-Wen
CW
Lin
Institute of Clinical Medicine, College of Medicine, National Cheng-Kung University, Tainan 701, Taiwan.
Yi-Ying
YY
Wu
Institute of Chemistry, Academia Sinica 115, Taipei, Taiwan.
Yu-Ju
YJ
Chen
Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, School of Pharmacy, Taipei Medical University 110, Taipei, Taiwan.
Chia-Li
CL
Han
Department of Pathology and Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
Yih-leong
YL
Chang
Department of Pathology and Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
Chen-Tu
CT
Wu
Department of Medical Research, Taichung Veterans General Hospital, Taichung 407, Taiwan.
Tzu-Hung
TH
Hsiao
Institute of Clinical Medicine, College of Medicine, National Cheng-Kung University, Tainan 701, Taiwan.
Tse-Ming
TM
Hong
Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan.|Institute of Biomedical Science, Academia Sinica, Taipei 115, Taiwan.|NTU Center for Genomic Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan.|Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
Pan-Chyr
PC
Yang
D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology* / Q000235:genetics / Q000556:secondary; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004705:Endocytosis; D004734:Energy Metabolism; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D005838:Genotype; D064593:Heterografts; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008207:Lymphatic Metastasis; D008297:Male; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D063154:Mitochondrial Dynamics / Q000187:drug effects; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D021381:Protein Transport; D040901:Proteomics / Q000379:methods; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection
D033681:Mitochondrial Membrane Transport Proteins; D004815:Epidermal Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors; D020558:GTP Phosphohydrolases; C470017:Mfn1 protein, human
EGFR; cancer metastasis; mitochondria dynamics