The stress sensor GCN2 differentially controls ribosome biogenesis in colon cancer according to the nutritional context.
Marie PiecykMouna TrikiPierre-Alexandre LavalCedric DuretJoelle FauvreLaura CussonneauChristelle MachonJerôme GuittonNicolas RamaBenjamin GibertGabriel IchimFrederic CatezFleur BourdelaisSebastien DurandJean-Jacques DiazIsabelle CosteToufic RennoSerge N ManieNicolas AznarStephane AnsieauCarole Ferraro-PeyretCédric ChaverouxPublished in: Molecular oncology (2023)
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 general control non-derepressible 2 (GCN2; also known as eIF-2-alpha kinase 4) represses the expression of the precursor of ribosomal RNA (rRNA), 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, a cell-autonomous GCN2 activity supports cell proliferation by stimulating 47S rRNA transcription, independently of the canonical integrated stress response (ISR) axis. Impairment of GCN2 activity prevents nuclear translocation of methionyl-tRNA synthetase (MetRS), resulting in nucleolar stress, mTORC1 inhibition and, ultimately, autophagy induction. Inhibition of the GCN2-MetRS axis drastically improves the cytotoxicity of RNA polymerase I (RNA pol I) inhibitors, including the first-line chemotherapy oxaliplatin, on patient-derived COAD tumoroids. Our data thus reveal that GCN2 differentially controls ribosome biogenesis according to the nutritional context. Furthermore, pharmacological co-inhibition of the two GCN2 branches and RNA pol I activity may represent a valuable strategy for elimination of proliferative and metabolically-stressed COAD cells.
Keyphrases
- single cell
- cell death
- cell proliferation
- cell therapy
- amino acid
- cell fate
- poor prognosis
- stem cells
- signaling pathway
- cell cycle arrest
- gene expression
- long non coding rna
- cell cycle
- tyrosine kinase
- genome wide
- mesenchymal stem cells
- big data
- data analysis
- binding protein
- rectal cancer
- deep learning
- protein kinase
- quality control