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

Grozdanić, Marija (author), Sobotič, Barbara (author), Biasizzo, Monika (author), Sever, Tilen (author), Vidmar, Robert (author), Vizovišek, Matej (author), Turk, Boris (author), Fonović, Marko (author)

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 transducer and activator of transcription 3 (STAT3) in cells that express the truncated EGFR protein and suggest that these phenomena cause resistance to EGFR inhibitors.

• Language: English
• Keywords: cancer, cysteine cathepsin, cathepsin L, EGFR, extracellular cleavage, resistance to TKIs
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FKKT - Faculty of Chemistry and Chemical Technology
• Publication status: Published
• Publication version: Version of Record
• Year: 2024
• Number of pages: Str. 283–296
• Numbering: Vol. 405, iss. 4
• PID: 20.500.12556/RUL-155448
• UDC: 577.2
• ISSN on article: 1431-6730
• DOI: 10.1515/hsz-2023-0213
• COBISS.SI-ID: 171358723
• Publication date in RUL: 02.04.2024

Record is a part of a journal

• Title: Biological chemistry
• Shortened title: Biol. chem.
• Publisher: De Gruyter
• ISSN: 1431-6730
• COBISS.SI-ID: 1541908

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Projects

• Funder: ARRS - Slovenian Research Agency
• Project number: P1-0140
• Name: Proteoliza in njena regulacija pri zdravju in boleznih

• Funder: ARRS - Slovenian Research Agency
• Project number: J1-1710
• Name: Vloga cisteinskih katepsinov pri aktivaciji komplementa pri raku