Modulating the structure of EGFR with UV light: new possibilities in cancer therapy
Manuel Correia1, Viruthachalam Thiagarajan2, Isabel Coutinho3
1Department of Physics and Nanotechnology, Aalborg University, Aalborg, Denmark.
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.
Insights
UVB light alters the structure of epidermal growth factor receptor (EGFR), disabling its signaling pathway. This photonic technology shows promise for cancer treatment by blocking a key receptor involved in tumor progression.
Area of Science:
- Biophysics
- Photochemistry
- Oncology
Background:
- Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase crucial for cell functions.
- EGFR overactivation is linked to tumor progression and cancer development.
- Previous research indicated low-dose UVB halts EGFR signaling in cancer cells.
Purpose of the Study:
- To investigate the molecular mechanisms by which UVB light affects the structure of EGFR.
- To determine if UVB-induced structural changes in EGFR impact its binding capabilities.
- To assess the potential of UVB as a therapeutic strategy for EGFR-driven cancers.
Main Methods:
- UVB illumination of soluble EGFR (sEGFR).
- Analysis of protein conformational changes using fluorescence spectroscopy, circular dichroism, and thermal studies.
- Assessment of photoproduct formation (dityrosine, kynurenine).
- Immunoassay using a monoclonal antibody that competes with EGF for EGFR binding.
Main Results:
- UVB illumination induced significant protein conformational changes in sEGFR.
- Disulphide bridges were broken, and photoproducts like dityrosine and kynurenine were formed.
- UVB light altered the EGF binding site structure, impairing antibody binding.
- Structural changes were observed at UVB irradiance levels comparable to solar UVB.
Conclusions:
- UVB light induces structural modifications in EGFR, affecting its extracellular domain and binding site.
- These UVB-induced structural changes disrupt EGFR's ability to bind EGF and related antibodies.
- Photonic inactivation of EGFR via UVB presents a potential novel therapeutic approach for cancer treatment.
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