Document Type
Article
Publication Date
3-10-2025
Identifier
DOI: 10.1038/s41467-025-57539-6; PMCID: PMC11894096
Abstract
Missense mutations in the TP53 (p53) gene have been linked to malignant progression. However, our in-silico analyses reveal that hepatocellular carcinoma (HCC) patients with mutant p53 (mutp53) have better overall survival compared to those with p53-null (p53null) HCC, unlike other cancer types. Given the historical use of sorafenib (SOR) monotherapy for advanced HCC, we hypothesize that mutp53 increases sensitivity to SOR, a multikinase inhibitor that induces endoplasmic reticulum (ER) stress. Here we show that mutp53 inhibits stress granule (SG) formation by binding to an ER stress sensor, PKR-like ER kinase (PERK), and a key SG component, GAP SH3 domain-binding protein 1 (G3BP1), contributing to increased sensitivity of SG-competent cells and xenografts to ER stress inducers including SOR. Our study identifies a unique vulnerability imposed by mutp53, suggesting mutp53 as a biomarker for ER stress-inducing agents and highlighting the importance of SG inhibition for cancer treatment.
Journal Title
Nat Commun
Volume
16
Issue
1
First Page
2365
Last Page
2365
MeSH Keywords
Humans; Tumor Suppressor Protein p53; Endoplasmic Reticulum Stress; Animals; Sorafenib; Carcinoma, Hepatocellular; Liver Neoplasms; RNA Recognition Motif Proteins; Cell Line, Tumor; eIF-2 Kinase; Poly-ADP-Ribose Binding Proteins; Mice; RNA Helicases; DNA Helicases; Stress Granules; Xenograft Model Antitumor Assays; Mice, Nude; Carrier Proteins; Mutation
PubMed ID
40064891
Keywords
Humans; Tumor Suppressor Protein p53; Endoplasmic Reticulum Stress; Animals; Sorafenib; Carcinoma, Hepatocellular; Liver Neoplasms; RNA Recognition Motif Proteins; Cell Line, Tumor; eIF-2 Kinase; Poly-ADP-Ribose Binding Proteins; Mice; RNA Helicases; DNA Helicases; Stress Granules; Xenograft Model Antitumor Assays; Mice, Nude; Carrier Proteins; Mutation
Recommended Citation
Thoenen E, Ranjan A, Parrales A, et al. Suppression of stress granule formation is a vulnerability imposed by mutant p53. Nat Commun. 2025;16(1):2365. Published 2025 Mar 10. doi:10.1038/s41467-025-57539-6
Comments
Grants and funding
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Publisher's Link: https://www.nature.com/articles/s41467-025-57539-6