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

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

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.

• Jezik: Angleški jezik
• Ključne besede: cancer, cysteine cathepsin, cathepsin L, EGFR, extracellular cleavage, resistance to TKIs
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FKKT - Fakulteta za kemijo in kemijsko tehnologijo
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2024
• Št. strani: Str. 283–296
• Številčenje: Vol. 405, iss. 4
• PID: 20.500.12556/RUL-155448
• UDK: 577.2
• ISSN pri članku: 1431-6730
• DOI: 10.1515/hsz-2023-0213
• COBISS.SI-ID: 171358723
• Datum objave v RUL: 02.04.2024

Gradivo je del revije

• Naslov: Biological chemistry
• Skrajšan naslov: Biol. chem.
• Založnik: De Gruyter
• ISSN: 1431-6730
• COBISS.SI-ID: 1541908

Licence

• Licenca: CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by/4.0/deed.sl
• Opis: To je standardna licenca Creative Commons, ki daje uporabnikom največ možnosti za nadaljnjo uporabo dela, pri čemer morajo navesti avtorja.

Projekti

• Financer: ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
• Številka projekta: P1-0140
• Naslov: Proteoliza in njena regulacija pri zdravju in boleznih

• Financer: ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
• Številka projekta: J1-1710
• Naslov: Vloga cisteinskih katepsinov pri aktivaciji komplementa pri raku