Pré-Publication, Document De Travail Année : 2023

Targeting the cell and non-cell autonomous regulation of 47S synthesis by GCN2 in colon cancer

Marie Piecyk
  • Fonction : Auteur
Mouna Triki
  • Fonction : Auteur
Pierre-Alexandre Laval
  • Fonction : Auteur
Cedric Duret
  • Fonction : Auteur
Joelle Fauvre
  • Fonction : Auteur
Laura Cussonneau
  • Fonction : Auteur
Christelle Machon
  • Fonction : Auteur
Fleur Bourdelais
  • Fonction : Auteur
Sebastien Durand
N Aznar
Carole Ferraro-Peyret
  • Fonction : Auteur

Résumé

Abstract Nutrient availability is a key determinant of tumor cell behavior. While nutrient-rich conditions favor proliferation and tumor growth, scarcity, and particularly glutamine starvation, promotes cell dedifferentiation and chemoresistance. Here, linking ribosome biogenesis plasticity with tumor cell fate, we uncover that the amino acid sensor GCN2 represses the expression of the precursor of ribosomal RNA, 47S, under metabolic stress. We show that blockade of GCN2 triggers cell death by an irremediable nucleolar stress and subsequent TP53-mediated apoptosis in patient-derived models of colon adenocarcinoma (COAD). In nutrient-rich conditions, GCN2 activity supports cell proliferation through the transcription stimulation of 47S rRNA, independently of the canonical ISR axis. However, impairment of GCN2 activity prevents nuclear translocation of the methionyl tRNA synthetase (MetRS) underlying the generation of a nucleolar stress, mTORC1 inhibition and autophagy induction. Inhibition of the GCN2-MetRS axis drastically improves the cytotoxicity of RNA pol I inhibitors, including the first-line chemotherapy oxaliplatin, on patient-derived COAD tumoroids. Our data thus reveal that GCN2 differentially controls the ribosome biogenesis according the nutritional context. Furthermore, pharmacological co-inhibition of the two GCN2 branches and the RNA pol I activity may represent a valuable strategy for elimination of proliferative and metabolically-stressed COAD cell.

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Dates et versions

hal-05008872 , version 1 (27-03-2025)

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Marie Piecyk, Mouna Triki, Pierre-Alexandre Laval, Cedric Duret, Joelle Fauvre, et al.. Targeting the cell and non-cell autonomous regulation of 47S synthesis by GCN2 in colon cancer. 2025. ⟨hal-05008872⟩
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