Abstract
The epidermal growth factor receptor (EGFR) is a member of the ErbB family of receptor tyrosine kinases. EGFR is activated upon binding to e.g. epidermal growth factor (EGF), leading to cell survival, proliferation and migration. EGFR overactivation is associated with tumor progression. We have previously shown that low dose UVB illumination of cancer cells overexpressing EGFR prior to adding EGF halted the EGFR signaling pathway. We here show that UVB illumination of the extracellular domain of EGFR (sEGFR) induces protein conformational changes, disulphide bridge breakage and formation of tryptophan and tyrosine photoproducts such as dityrosine, N-formylkynurenine and kynurenine. Fluorescence spectroscopy, circular dichroism and thermal studies confirm the occurrence of conformational changes. An immunoassay has confirmed that UVB light induces structural changes in the EGF binding site. A monoclonal antibody which competes with EGF for binding sEGFR was used. We report clear evidence that UVB light induces structural changes in EGFR that impairs the correct binding of an EGFR specific antibody that competes with EGF for binding EGFR, confirming that the 3D structure of the EGFR binding domain suffered conformational changes upon UV illumination. The irradiance used is in the same order of magnitude as the integrated intensity in the solar UVB range. The new photonic technology disables a key receptor and is most likely applicable to the treatment of various types of cancer, alone or in combination with other therapies.
Highlights
The ErbB family of receptor tyrosine kinases (RTKs) plays a key role in regulating normal cellular processes such as cell survival, proliferation and migration [1,2] and have a critical role in the development and progression of cancers [3]
epidermal growth factor receptor (EGFR) binding to ligands such as epidermal growth factor (EGF) or transforming growth factor alpha (TGF-a) leads to receptor dimerization and to the activation of the intracellular tyrosine kinase domain [1,2]
We have previously reported that UVB illumination (280 nm, 0.35 W/m2 for 30 min) of cancer cells overexpressing EGFR led to the arrest of the EGFR signaling pathway [9]
Summary
The ErbB family of receptor tyrosine kinases (RTKs) plays a key role in regulating normal cellular processes such as cell survival, proliferation and migration [1,2] and have a critical role in the development and progression of cancers [3]. EGFR binding to ligands such as epidermal growth factor (EGF) or transforming growth factor alpha (TGF-a) leads to receptor dimerization and to the activation of the intracellular tyrosine kinase domain [1,2]. Typical chemotherapeutical agents are EGFR tyrosine kinase inhibitors which compete with ATP at the intracellular tyrosine kinase domain, and monoclonal antibodies (mAbs) that prevent ligand-binding or receptor dimerization. Blocking the binding of EGF to EGFR can abolish cancer proliferation, invasion, metastasis, angiogenesis and inhibition of apoptosis [8]
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