Cytosolic malic enzyme and glucose‐6‐phosphate dehydrogenase modulate redox balance in NSCLC with acquired drug resistance

Author:

Ran Maoxin1,Zhou Yan1,Guo Yizhen1,Huang Ding1,Zhang Shao‐Lin2,Tam Kin Yip1ORCID

Affiliation:

1. Cancer Centre, Faculty of Health Sciences University of Macau, Avenida de Universidade China

2. School of Pharmaceutical Sciences, Chongqing Key Laboratory of Natural Product Synthesis and Drug Research Chongqing University China

Abstract

Lung cancer cells often show elevated levels of reactive oxygen species (ROS) and nicotinamide adenine dinucleotide phosphate (NADPH). However, the connections between deregulated redox homeostasis in different subtypes of lung cancer and acquired drug resistance in lung cancer have not yet been fully established. Herein, we analyzed different subtypes of lung cancer data reported in the Cancer Cell Line Encyclopedia (CCLE) database, the Cancer Genome Atlas program (TCGA), and the sequencing data obtained from a gefitinib‐resistant non‐small‐cell lung cancer (NSCLC) cell line (H1975GR). Using flux balance analysis (FBA) model integrated with multiomics data and gene expression profiles, we identified cytosolic malic enzyme 1 (ME1) and glucose‐6‐phosphate dehydrogenase as the major contributors to the significantly upregulated NADPH flux in NSCLC tissues as compared with normal lung tissues, and gefitinib‐resistant NSCLC cell line as compared with the parental cell line. Silencing the gene expression of either of these two enzymes in two osimertinib‐resistant NSCLC cell lines (H1975OR and HCC827OR) exhibited strong antiproliferative effects. Our findings not only underscored the pivotal roles of cytosolic ME1 and glucose‐6‐phosphate dehydrogenase in regulating redox states in NSCLC cells but also provided novel insights into their potential roles in drug‐resistant NSCLC cells with disturbed redox states.

Funder

Fundo para o Desenvolvimento das Ciências e da Tecnologia

Universidade de Macau

Publisher

Wiley

Subject

Cell Biology,Molecular Biology,Biochemistry

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