Mitochondrial translocation of EGFR regulates mitochondria dynamics and promotes metastasis in NSCLC
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Ting-Fang Che1, Ching-Wen Lin2, Yi-Ying Wu5, Yu-Ju Chen6, Chia-Li Han7, Yih-leong Chang8, Chen-Tu Wu8, Tzu-Hung Hsiao9, Tse-Ming Hong5,*, Pan-Chyr Yang1,2,3,4,*
1Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan
2Institute of Biomedical Science, Academia Sinica, Taipei 115, Taiwan
3NTU Center for Genomic Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan
4Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan
5Institute of Clinical Medicine, College of Medicine, National Cheng-Kung University, Tainan 701, Taiwan
6Institute of Chemistry, Academia Sinica 115, Taipei, Taiwan
7Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, School of Pharmacy, Taipei Medical University 110, Taipei, Taiwan
8Department of Pathology and Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei 100, Taiwan
9Department of Medical Research, Taichung Veterans General Hospital, Taichung 407, Taiwan
*These authors have contributed equally to this work
Pan-Chyr Yang, e-mail: firstname.lastname@example.org
Tse-Ming Hong, e-mail: email@example.com
Keywords: cancer metastasis, EGFR, mitochondria dynamics
Received: May 19, 2015 Accepted: October 06, 2015 Published: October 19, 2015
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.
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