The E3 ubiquitin ligase NEDD4 regulates chemoresistance to 5-fluorouracil in colorectal cancer cells by altering JNK signalling

Anand, Sushma; Nedeva, Christina; Chitti, Sai Vara Prasad; Fonseka, Pamali; Kang, Taeyoung; Gangoda, Lahiru; Tabassum, Nishat; Abdirahman, Suad; Arumugam, Thiruma; Putoczki, Tracy L; Kumar, Sharad; Mathivanan, Suresh

doi:10.1038/s41419-023-06349-z

The E3 ubiquitin ligase NEDD4 regulates chemoresistance to 5-fluorouracil in colorectal cancer cells by altering JNK signalling

journal contribution

posted on 2025-01-12, 23:42 authored by Sushma Anand, Christina Nedeva, Sai Vara Prasad ChittiSai Vara Prasad Chitti, Pamali FonsekaPamali Fonseka, Taeyoung KangTaeyoung Kang, Lahiru GangodaLahiru Gangoda, Nishat TabassumNishat Tabassum, Suad Abdirahman, Thiruma ArumugamThiruma Arumugam, Tracy L Putoczki, Sharad Kumar, Suresh MathivananSuresh Mathivanan

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.

Funding

SM is supported by the Australian Research Council Future Fellowship (FT180100333) but the project was not funded by basic science grants. SK was supported by an NHMRC Senior Principal Research Fellowship (GNT1103006) and an NHMRC L3 Investigator Grant (2007739). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

History

Publication Date

2023-12-14

Journal

Cell Death and Disease

Volume

14

Issue

12

Article Number

828

Pagination

11p.

Publisher

Springer Nature

ISSN

2041-4889

Rights Statement

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