Mitochondrial translocation of EGFR regulates mitochondria dynamics and promotes metastasis in NSCLC

Abstract

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.

A Novel Tumor-Suppressor, CDH18, Inhibits Glioma Cell Invasiveness Via UQCRC2 and Correlates with the Prognosis of Glioma Patients

“…In recent years, a growing number of studies provided new insight into the role of mitochondria in cancer and demonstrated that impaired bioenergetic function of mitochondria is a hallmark of tumorigenesis [32,33]. It has been reported that mitochondrial alteration is correlated with cancer cell motility and invasiveness, as well as chemo-resistance [34][35][36]. We inferred that CDH18 might influence the function of mitochondria via UQCRC2, and thus inhibited the invasiveness and chemoresistance of glioma cells.…”

The mitochondrial dynamics in cancer and immune-surveillance

“…In this case, mitochondria need to fragment, in a Drp1-dependent way, in order to be transported and accumulate at the cell leading-edge, where they promote local ATP production, essential for lamellipodia formation, cell migration and metastasis formation [71]. The same was shown in non-small cell lung cancer (NSLCC) [72], in epithelial cancer cells [73] and malignant oncocytic thyroid tumors [70]. Interestingly, also TME-derived hypoxia is able to regulate both glioblastoma and breast cancer cell migration by promoting Drp1 transcription and stimulating mitochondrial fission [74,75].…”

Mitochondrial Hormone Receptors - an Emerging Field of Signaling in the Cell’s Powerhouse

“…EGFR (epidermal growth factor receptor) is an example for a receptor tyrosine kinase that has been shown to be translocated to mitochondria [22]. This finding differs from the previously discussed cases insofar as the ligand is not a low-molecular weight molecule such as steroids, T3 and the vitamin D 3 hormone, but represents a peptide of 53 amino acids.…”

“…Mitochondrial EGFR has been studied in detail in non-small-cell lung cancer cells. It was shown to be internalized by endocytosis and, thereafter, attached to mitochondria [22]. The translocation was stimulated by EGF.…”

“…By interfering with the mitochondrial fusion factor Mfn1, it shifted the fusion/fission balance towards fission [22]. Notably, the inhibition of mitochondrial fusion leads to facilitated redistribution of the smaller mitochondria within cells, which would be impossible with the longer organelles that can, in the extreme, fuse to large networks.…”