Research Information System
MICROCHEMICAL JOURNAL, 2025 (SCI-Expanded)
Aims: Today's omics technologies enable complex analyses to better understand phenotypes. Characterization of metabolic phenotypes requires the identification of large numbers of proteins, metabolites and simultaneous as well as comprehensive analysis of their turnover rates. In this study, alterations in the phenotype of human colon adenocarcinoma cell lines (Caco-2) resulting from resistance to chemotherapeutics were investigated by multiomics analysis. Main methods: Drug resistance to cisplatin (CIS) and 5-fluorouracil (5-FU) was induced by long-term exposure of Caco-2 cells to minimum lethal dose. Integrated omics analysis was performed using proteomics, metabolomics, lipidomics and O-18-based fluxomics analyses. Key findings: As a result of aforementioned analyses, 650 proteins, more than 300 metabolites/lipids were determined and the turnover rates of a total of 38 metabolites, including intermediates in the Krebs Cycle, amino acids, fatty acids and phosphonucleotides, were calculated. Multivariate analyses revealed significant differences in phenotype between the cell group induced with either chemotherapeutic agent and the control cells. The joint pathway analysis performed by profiling metabolites, lipids and proteins with significant (p < 0.05) differences between groups showed that malate-aspartate shuttle, amino acid, ammonia metabolism, glucose-alanine and urea cycle pathways were altered due to resistance to the chemotherapeutic agent. Significance: Data from comprehensive omics (proteomics, metabolomics, lipidomics and fluxomics) studies of Caco-2 cells induced either with CIS or 5-FU, showed that resistance to chemotherapeutics is due to differences in cell dynamics. Furthermore, the phenotype behind drug resistance depends on the chemotherapeutic agent.