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Triomics Analysis of Imatinib-Treated Myeloma Cells Connects Kinase Inhibition to RNA Processing and Decreased Lipid Biosynthesis

Reputable Mentor II
Reputable Mentor II
Susanne B. Breitkopf, Min Yuan, Katja P. Helenius, Costas A. Lyssiotis and John M. Asara
Analytical Chemistry, 2015, 87 (21), pp 10995–11006
The combination of metabolomics, lipidomics, and phosphoproteomics that incorporates triple stable isotope labeling by amino acids in cell culture (SILAC) protein labeling, as well as 13C in vivo metabolite labeling, was demonstrated on BCR−ABL-positive H929 multiple myeloma cells. From 11 880 phosphorylation sites, we confirm that H929 cells are primarily signaling through the BCR−ABL−ERK pathway, and we show that imatinib treatment not only down regulates phosphosites in this pathway but also upregulates phosphosites on proteins involved in RNA expression. Metabolomics analyses reveal that BCR−ABL−ERK signaling in H929 cells drives the pentose phosphate pathway (PPP) and RNA biosynthesis, where pathway inhibition via imatinib results in marked PPP impairment and an accumulation of RNA nucleotides and negative regulation of mRNA. Lipidomics data also show an overall reduction in lipid biosynthesis and fatty acid incorporation with a significant decrease in lysophospholipids. RNA immunoprecipitation studies confirm that RNA degradation is inhibited with short imatinib treatment and transcription is inhibited upon long imatinib treatment, validating the triomics results. These data show the utility of combining mass spectrometry-based “-omics” technologies and reveals that kinase inhibitors may not only downregulate phosphorylation of their targets but also induce metabolic events via increased phosphorylation of other cellular components.
Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, United States Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, United States David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States Department of Molecular and Integrative Physiology and Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States
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‎10-15-2021 10:42 AM
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