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Suppression of stress granule formation is a vulnerability imposed by mutant p53

Author

Listed:
  • Elizabeth Thoenen

    (Children’s Mercy Research Institute)

  • Atul Ranjan

    (Children’s Mercy Research Institute)

  • Alejandro Parrales

    (Children’s Mercy Research Institute)

  • Shigeto Nishikawa

    (Children’s Mercy Research Institute)

  • Dan A. Dixon

    (University of Arkansas for Medical Sciences)

  • Sugako Oka

    (Kyushu University)

  • Tomoo Iwakuma

    (Children’s Mercy Research Institute
    University of Kansas Medical Center)

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.

Suggested Citation

  • Elizabeth Thoenen & Atul Ranjan & Alejandro Parrales & Shigeto Nishikawa & Dan A. Dixon & Sugako Oka & Tomoo Iwakuma, 2025. "Suppression of stress granule formation is a vulnerability imposed by mutant p53," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57539-6
    DOI: 10.1038/s41467-025-57539-6
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