Insights Into the Mechanism of Anticancer Drug Imatinib Revealed Through Multi-Omic Analyses in Yeast
Küçük Resim Yok
Tarih
2020
Dergi Başlığı
Dergi ISSN
Cilt Başlığı
Yayıncı
Mary Ann Liebert, Inc
Erişim Hakkı
info:eu-repo/semantics/closedAccess
Özet
Imatinib mesylate is a receptor tyrosine kinase inhibitor drug with broad applications in cancer therapeutics, for example, in chronic myeloid leukemia and gastrointestinal stromal tumors. In this study, new multi-omics findings in yeast on the mechanism of imatinib are reported, using the model organismSaccharomyces cerevisiae. Whole-genome analysis of the transcriptional response of yeast cells following long-term exposure to imatinib, flux-balance analysis (FBA), and modular analysis of protein/protein interaction network consisting of proteins encoded by differentially expressed genes (DEGs) were performed. DEGs indicated that carbon, nitrogen, starch, sucrose, glyoxylate/dicarboxylate metabolism, valine and leucine degradation, and tricarboxylic acid cycle (TCA) were significantly upregulated. By contrast, ribosome biogenesis, pentose/glucuronate interconversion, tryptophan/pyruvate metabolic pathways, and meiosis were significantly downregulated. FBA revealed that a large set of metabolic pathways was altered by imatinib to compensate cancer-associated metabolic changes. Integration of transcriptome and interactome (protein/protein interactions) data helped to identify the core regulatory genes and pathways through elucidation of the active subnetworks. It appears that imatinib may also contribute to antitumoral immune response in the tumor microenvironment and most of the metabolic rearrangements are at posttranscriptional level. Furthermore, additional support for possible contribution of thiamine/pyridoxal phosphate biosynthesis and mitogen-activated protein kinase pathway to drug resistance is noted. This report advances multi-omics understanding of the mechanism of imatinib, and by extension, offers new molecular avenues toward precision medicine and discovery of novel drug targets in cancer therapeutics.
Açıklama
Anahtar Kelimeler
İmatinib, Cancer, Multi-Omics, Yeast, Protein, Protein İnteractions, Systems Biology, Kinase Inhibitor Imatinib, Amino-Acid-Metabolism, Functional-Analysis, Induced Apoptosis, Leukemia, Resistance, Cancer, Pathway, Activation, Mutations
Kaynak
Omics-A Journal of Integrative Biology
WoS Q Değeri
Q2
Scopus Q Değeri
Q2
Cilt
24
Sayı
11
