The E3 ubiquitin ligase NEDD4 regulates chemoresistance to 5-fluorouracil in colorectal cancer cells by altering JNK signalling
Details
Publication Year 2023-12-14,Volume 14,Issue #12,Page 828
Journal Title
Cell Death & Disease
Publication Type
Research article
Abstract
Colorectal cancer (CRC) is the second leading cause of cancer deaths. Though chemotherapy is the main treatment option for advanced CRC, patients invariably acquire resistance to chemotherapeutic drugs and fail to respond to the therapy. Although understanding the mechanisms regulating chemoresistance has been a focus of intense research to manage this challenge, the pathways governing resistance to drugs are poorly understood. In this study, we provide evidence for the role of ubiquitin ligase NEDD4 in resistance developed against the most commonly used CRC chemotherapeutic drug 5-fluorouracil (5-FU). A marked reduction in NEDD4 protein abundance was observed in a panel of CRC cell lines and patient-derived xenograft samples that were resistant to 5-FU. Knockout of NEDD4 in CRC cells protected them from 5-FU-mediated apoptosis but not oxaliplatin or irinotecan. Furthermore, NEDD4 depletion in CRC cells reduced proliferation, colony-forming abilities and tumour growth in mice. Follow-up biochemical analysis highlighted the inhibition of the JNK signalling pathway in NEDD4-deficient cells. Treatment with the JNK activator hesperidin in NEDD4 knockout cells sensitised the CRC cells against 5-FU. Overall, we show that NEDD4 regulates cell proliferation, colony formation, tumour growth and 5-FU chemoresistance in CRC cells.
Publisher
Springer Nature
Keywords
Humans; Animals; Mice; *Fluorouracil/pharmacology/therapeutic use; Cell Line, Tumor; Drug Resistance, Neoplasm; Ubiquitin-Protein Ligases/genetics/therapeutic use; Mice, Knockout; Cell Proliferation; *Colorectal Neoplasms/drug therapy/genetics/metabolism
Department(s)
Laboratory Research
Open Access at Publisher's Site
https://doi.org/10.1038/s41419-023-06349-z
Terms of Use/Rights Notice
Refer to copyright notice on published article.


Creation Date: 2024-01-16 04:29:25
Last Modified: 2024-01-16 04:53:14

© 2024 The Walter and Eliza Hall Institute of Medical Research. Access to this website is subject to our Privacy Policy and Terms of Use

An error has occurred. This application may no longer respond until reloaded. Reload 🗙