Quantitative Proteomic Approach Reveals Altered Metabolic Pathways in Response to the Inhibition of Lysine Deacetylases in A549 Cells under Normoxia and Hypoxia - Université Grenoble Alpes Accéder directement au contenu
Article Dans Une Revue International Journal of Molecular Sciences Année : 2021

Quantitative Proteomic Approach Reveals Altered Metabolic Pathways in Response to the Inhibition of Lysine Deacetylases in A549 Cells under Normoxia and Hypoxia

Alfonso Martín-Bernabé
Josep Tarragó-Celada
Valérie Cunin
  • Fonction : Auteur
Sylvie Michelland
  • Fonction : Auteur
Roldán Cortés
  • Fonction : Auteur
Johann Poignant
  • Fonction : Auteur
Cyril Boyault
  • Fonction : Auteur
Walid Rachidi
  • Fonction : Auteur
Marta Cascante

Résumé

Growing evidence is showing that acetylation plays an essential role in cancer, but studies on the impact of KDAC inhibition (KDACi) on the metabolic profile are still in their infancy. Here, we analyzed, by using an iTRAQ-based quantitative proteomics approach, the changes in the proteome of KRAS-mutated non-small cell lung cancer (NSCLC) A549 cells in response to trichostatin-A (TSA) and nicotinamide (NAM) under normoxia and hypoxia. Part of this response was further validated by molecular and biochemical analyses and correlated with the proliferation rates, apoptotic cell death, and activation of ROS scavenging mechanisms in opposition to the ROS production. Despite the differences among the KDAC inhibitors, up-regulation of glycolysis, TCA cycle, oxidative phosphorylation and fatty acid synthesis emerged as a common metabolic response underlying KDACi. We also observed that some of the KDACi effects at metabolic levels are enhanced under hypoxia. Furthermore, we used a drug repositioning machine learning approach to list candidate metabolic therapeutic agents for KRAS mutated NSCLC. Together, these results allow us to better understand the metabolic regulations underlying KDACi in NSCLC, taking into account the microenvironment of tumors related to hypoxia, and bring new insights for the future rational design of new therapies.

Dates et versions

hal-04555737 , version 1 (23-04-2024)

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Citer

Alfonso Martín-Bernabé, Josep Tarragó-Celada, Valérie Cunin, Sylvie Michelland, Roldán Cortés, et al.. Quantitative Proteomic Approach Reveals Altered Metabolic Pathways in Response to the Inhibition of Lysine Deacetylases in A549 Cells under Normoxia and Hypoxia. International Journal of Molecular Sciences, 2021, 22 (7), pp.3378. ⟨10.3390/ijms22073378⟩. ⟨hal-04555737⟩

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