PR001674 (Project)

Description:Lung cancer is the second most common cancer and the leading cause of cancer-related deaths worldwide. Chemotherapy resistance in lung cancer is one of the major characteristics of an aggressive phenotype with poor prognosis. Therefore, there is a critical need to explore the significant molecular changes associated with resistance to conventional chemotherapy, and identify potential therapeutic targets for treatment of resistant lung cancer. In this study, we have performed comprehensive quantitative proteomics and metabolomics analysis of non-small cell lung cancer cells (A549-P) and doxorubicin resistant A549 cells (A549-R), using state-of-the-art Trapped Ion Mobility Spectroscopy, Time-of-Flight Mass Spectrometry (TIMS-TOF-MS). The results revealed 30 dysregulated proteins and 37 significantly altered metabolites in A549-R cells compared to A549-P cells. Among the significantly upregulated proteins are liver carboxylesterase 1, anterior gradient protein 2 homolog and nicotinamide phosphoribosyltransferase. A group of the upregulated proteins are endogenous and xenobiotic-metabolizing enzymes, including UDP-glucuronosyltransferase 1-6, CES1, and epoxide hydrolase 1. While Importin, ATP-citrate synthase and CTP synthase are downregulated. The significantly altered metabolites include sepiapterin, glutathione, glycine, pyridine and niacinamide. The performed multi-omics integrated analysis revealed the involvement of purine and glutathione metabolism, ABC transporters, citric acid cycle in the development of resistance in A549 cells, besides the involvement of energy metabolism, pathways related to cancer progression, invasion and migration, and redox homeostasis. Collectively, this exploratory study effectively revealed the significantly dysregulated proteins and metabolites in doxorubicin resistant A549 cells and shed the light on potential biomarkers for chemotherapy resistant non-small cell lung cancer. In addition, multi-omics integrated analysis elucidates the involved pathways in resistance including pathways related to progression and invasion which would improve prognosis and open the door for new potential therapeutic targets.