Abstract
The Epidermal Growth Factor Receptor (EGFR) and its mutations contribute in various ways to tumorigenesis and biology of human cancers. They are associated with tumor proliferation, progression, drug resistance and the process of apoptosis. There are also reports that overexpression and activation of wild-type EGFR may lead to cell apoptosis. To study this phenomenon, we overexpressed in an AD293 cell line two most frequently observed forms of the EGFR receptor: wild-type and the constitutively active mutant–EGFR variant III (EGFRvIII). Then, we compared the effect of EGF stimulation on cell viability and downstream EGFR signaling. AD293 cells overexpressing wild-type EGFR, despite a significant proliferation increase in serum supplemented medium, underwent apoptosis after EGF stimulation in serum free conditions. EGFRvIII expressing cells, however, were unaffected by either serum starvation or EGF treatment. The effect of EGF was completely neutralized by tyrosine kinase inhibitors (TKIs), indicating the specificity of this observation. Moreover, apoptosis was not prevented by inhibiting EGFR downstream proteins (PI3K, AKT and mTOR). Here we showed another EGFR function, dependent on environmental factors, which could be employed in therapy and drug design. We also proposed a new tool for EGFR inhibitor analysis.
Highlights
Epidermal Growth Factor Receptor (EGFR) amplification or mutation occurs in many different tumors [1]
Phosphorylation of EGFR at tyrosine 1173 was observed in all modified cell lines; importantly, EGFRwt phosphorylation was almost absent (Fig 1A)
In terms of proliferation in complete medium, we observed that EGFRwt-expressing cells had the highest division rate (P
Summary
Epidermal Growth Factor Receptor (EGFR) amplification or mutation occurs in many different tumors [1]. EGFR is a receptor tyrosine kinase (RTK) responsive to extracellular ligands such as EGF and TGF-α. One of its most frequent variants is Epidermal Growth Factor Receptor variant III (EGFRvIII), a truncated protein generated by in-frame deletion of exons 2–7, characterized by the absence of the ligand binding domain and constitutive, ligand-independent signaling [2]. Wild-type EGFR (EGFRwt) and EGFRvIII amplification frequently coincide [1,3], but whether this event influences a clinical outcome still remains unclear [4,5,6].
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