20.500.12556/RUL-155448 Cathepsin L-mediated EGFR cleavage affects intracellular signalling pathways in cancer 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. cancer cysteine cathepsin cathepsin L EGFR extracellular cleavage resistance to TKIs true false true Angleški jezik Ni določen Članek v reviji 2024-04-02 13:44:22 2024-04-02 13:44:23 2024-04-03 03:48:58 0000-00-00 00:00:00 2024 0 0 Str. 283–296 iss. 4 Vol. 405 2024 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 577.2 1431-6730 10.1515/hsz-2023-0213 171358723 10.1515_hsz-2023-0213_(1).pdf 10.1515_hsz-2023-0213_(1).pdf 1 7D87F8EC9F49CB6F6B1FC5F06A622069 dc4106d6b58b544e8dd53a8dfce2874b8ca484e64e449a16b63d111b2cc2a7f1 1a0eff57-f0e7-11ee-87d4-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=182337 https://www.degruyter.com/document/doi/10.1515/hsz-2023-0213/html 0 84e2c7e5-f0e6-11ee-87d4-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=182336 Fakulteta za kemijo in kemijsko tehnologijo 0 0 0