Cathepsin L-mediated EGFR cleavage affects intracellular signalling pathways in cancer

• Published in: Biological chemistry Vol. 405; no. 4; pp. 283 - 296
• Main Authors: Grozdanić, Marija, Sobotič, Barbara, Biasizzo, Monika, Sever, Tilen, Vidmar, Robert, Vizovišek, Matej, Turk, Boris, Fonović, Marko
• Format: Journal Article
• Language: English
• Published: Germany De Gruyter 25.04.2024; Walter de Gruyter GmbH
• Subjects: cancer; Cathepsin L; Cell viability; Cleavage; cysteine cathepsin; EGFR; Epidermal growth factor receptors; extracellular cleavage; Feedback loops; Growth factors; Inhibitors; Intracellular; Intracellular signalling; Kinases; Localization; Monoclonal antibodies; Phosphorylation; Positive feedback; Proteins; Proteolysis; resistance to TKIs; Signal transduction; Stat3 protein; Tumor microenvironment; Tumors; Tyrosine; Tyrosine kinase inhibitors; cancer; cathepsin L; EGFR; extracellular cleavage; cysteine cathepsin; resistance to TKIs
• ISSN: 1431-6730; 1437-4315; 1437-4315
• DOI: 10.1515/hsz-2023-0213

Proteolytic activity in the tumour microenvironment is an important factor in cancer development since it can also affect intracellular signalling pathways via positive feedback loops that result in either increased tumour growth or resistance to anticancer mechanisms. In this study, we demonstrated extracellular cathepsin L-mediated cleavage of epidermal growth factor receptor (EGFR) and identified the cleavage site in the extracellular domain after R224. To further evaluate the relevance of this cleavage, we cloned and expressed a truncated version of EGFR, starting at G225, in HeLa cells. We confirmed the constitutive activation of the truncated protein in the absence of ligand binding and determined possible changes in intracellular signalling. Furthermore, we determined the effect of truncated EGFR protein expression on HeLa cell viability and response to the EGFR inhibitors, tyrosine kinase inhibitor (TKI) erlotinib and monoclonal antibody (mAb) cetuximab. Our data reveal the nuclear localization and phosphorylation of EGFR and signal trancducer and activator of transcription 3 (STAT3) in cells that express the truncated EGFR protein and suggest that these phenomena cause resistance to EGFR inhibitors.