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,Johann Poignant,Walid Rachidi,Sylvie Michelland,Marta Cascante,Roldán Cortés,Michel Seve,Valérie Cunin,Sandrine Bourgoin-Voillard,Cyril Boyault,Josep Tarragó-Celada

doi:10.3390/ijms22073378

Abstract

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.

Highlights

IntroductionIntroduction conditions of the Creative CommonsLung cancer is the leading cause of cancer-related death worldwide, with an estimated upward trend of 2.1 million new cases and 1.8 million deaths per year (approximately18.4% of total cancer deaths) in 2018 [1]
Introduction conditions of the Creative CommonsLung cancer is the leading cause of cancer-related death worldwide, with an estimated upward trend of 2.1 million new cases and 1.8 million deaths per year in 2018 [1]
KDAC Inhibition Leads to Reduced Cell Proliferation by Inducing Apoptosis, Cell Cycle

Summary

Introduction

Introduction conditions of the Creative CommonsLung cancer is the leading cause of cancer-related death worldwide, with an estimated upward trend of 2.1 million new cases and 1.8 million deaths per year (approximately18.4% of total cancer deaths) in 2018 [1]. Lung cancer is the leading cause of cancer-related death worldwide, with an estimated upward trend of 2.1 million new cases and 1.8 million deaths per year Traditional therapies in NSCLC such as radiotherapy and platinum-based chemotherapy lack specificity and often cause severe side effects as they affect healthy cells [3]. To address this problem, targeted therapies and immunotherapies have emerged as a way to target cancer cells. Several studies have shown that mutations in KRAS play a critical role in metabolic reprogramming in multiple cancers, including lung cancer [7,8]

Methods

Results

Conclusion