| Title: |
Inhibiting translation elongation by reducing eIF5A activity induces feedback inhibition of initiation, limiting tumour cell proliferation. |
| Authors: |
Sfakianos, Aristeidis P; Raven, Rebecca M; Smith, Tom; Sun, Xiao-Ming; Mulroney, Thomas E; Pizzinga, Mariavittoria; Dezi, Veronica; Tenor, Angela Rubio; Stoneley, Mark; Cole, Cameron H; Al-Doori, Karam; Nur, Hashim Ahmed; Pennie, Rachel L; Powley, Ian; Officer-Jones, Leah; Sawarkar, Ritwick; Turner, Martin; MacFarlane, Marion; Sansom, Owen J; Bushell, Martin; Le Quesne, John; Harvey, Robert F; Willis, Anne E |
| Publisher Information: |
Springer Nature; //doi.org/10.1038/s41467-025-66531-z |
| Publication Year: |
2025 |
| Collection: |
Apollo - University of Cambridge Repository |
| Subject Terms: |
Eukaryotic Translation Initiation Factor 5A; Peptide Initiation Factors; Humans; Cell Proliferation; RNA-Binding Proteins; Phosphorylation; Cell Line; Tumor; Eukaryotic Initiation Factor-2; Feedback; Physiological; Peptide Chain Elongation; Translational; Neoplasms; Protein Biosynthesis; Signal Transduction; Mitochondria; Peptide Chain Initiation |
| Description: |
Acknowledgements: We thank the Flow Cytometry, Microscopy, Mass Spectrometry and Bioinformatics facility of MRC Toxicology Unit for their support throughout this study. A.P.S., is supported by is supported by Cancer Research UK Technology, UK Grant G108392, A.E.W. M.S., R.F.H., T.S. and A.R., are supported by the Medical Research Council, grant number MC_UP_A600_1023 (A.E.W.) T.E. M acknowledges funding from Wellcome Leap as part of the R3 Program. MB was funded by CRUK A29252 and A31287, OJS was funded by CRUK DRCQQR-May21\100002, A24388 and A31287, JPCLQ is funded by the Mazumdar-Shaw Molecular Pathology Chair endowment at the University of Glasgow, and CRUK EDDPGM-Nov21\100001. We also thank NHS Greater Glasgow and Clyde Biorepository, the Glasgow Tissue Research Facility, and the CRUK Scotland Institute Histology Facility. We would like to thank Rachel Grimley, Neil Jones, Nathan Breeds, Sheena Patel and Azadeh Bagherzadeh from Cancer Research Horizons for helpful discussions. ; Publication status: Published ; Cancer development is associated with dysregulation of the translatome, and targeting canonical eukaryotic initiation and elongation factors can offer treatment avenues for various neoplasms. Emerging evidence indicates that dysregulated mRNA elongation, involving alterations in eEF2 activity and eIF5A expression, also contributes to tumour cell growth. In this study, we investigate whether targeting eIF5A with the inhibitor GC7 is a viable strategy to curtail aberrant cell growth. Our findings demonstrate that inhibiting elongation by reducing eIF5A activity induces feedback inhibition of initiation through eIF2α phosphorylation, decreasing ternary complex formation and shutting down bulk protein synthesis. Employing dynamic SILAC, we identify proteins impacted by reduced eIF5A activity, and show their decreased translation results from feedback inhibition to initiation or other processes downstream of eIF5A. Decreased eIF5A activity impairs mitochondrial function, which activates signalling through ... |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/zip; application/pdf; text/xml |
| Language: |
English |
| Relation: |
66531; https://www.repository.cam.ac.uk/handle/1810/394687 |
| Availability: |
https://www.repository.cam.ac.uk/handle/1810/394687 |
| Accession Number: |
edsbas.B7B2F56 |
| Database: |
BASE |