Exosomes released by imatinib‑resistant K562 cells contain specific membrane markers, IFITM3, CD146 and CD36 and increase the survival of imatinib‑sensitive cells in the presence of imatinib
Language English Country Greece Media print-electronic
Document type Journal Article
PubMed
33491750
DOI
10.3892/ijo.2020.5163
Knihovny.cz E-resources
- Keywords
- chronic myeloid leukemia, imatinib mesylate, drug resistance, proteomics, exosome, tyrosine kinase inhibitor, surface marker,
- MeSH
- CD146 Antigen metabolism MeSH
- CD36 Antigens metabolism MeSH
- Apoptosis drug effects MeSH
- Fusion Proteins, bcr-abl antagonists & inhibitors genetics MeSH
- K562 Cells MeSH
- Drug Resistance, Neoplasm MeSH
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy genetics pathology MeSH
- Exosomes drug effects metabolism MeSH
- Imatinib Mesylate pharmacology therapeutic use MeSH
- Protein Kinase Inhibitors pharmacology therapeutic use MeSH
- Humans MeSH
- Membrane Proteins metabolism MeSH
- Cell Line, Tumor MeSH
- RNA-Binding Proteins metabolism MeSH
- Cell Survival drug effects MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- CD146 Antigen MeSH
- CD36 Antigens MeSH
- Fusion Proteins, bcr-abl MeSH
- BCR-ABL1 fusion protein, human MeSH Browser
- IFITM3 protein, human MeSH Browser
- Imatinib Mesylate MeSH
- Protein Kinase Inhibitors MeSH
- Membrane Proteins MeSH
- RNA-Binding Proteins MeSH
Chronic myeloid leukemia (CML) is a malignant hematopoietic disorder distinguished by the presence of a BCR‑ABL1 fused oncogene with constitutive kinase activity. Targeted CML therapy by specific tyrosine kinase inhibitors (TKIs) leads to a marked improvement in the survival of the patients and their quality of life. However, the development of resistance to TKIs remains a critical issue for a subset of patients. The most common cause of resistance are numerous point mutations in the BCR‑ABL1 gene, followed by less common mutations and multiple mutation-independent mechanisms. Recently, exosomes, which are extracellular vesicles excreted from normal and tumor cells, have been associated with drug resistance and cancer progression. The aim of the present study was to characterize the exosomes released by imatinib‑resistant K562 (K562IR) cells. The K562IR‑derived exosomes were internalized by imatinib‑sensitive K562 cells, which thereby increased their survival in the presence of 2 µM imatinib. The exosomal cargo was subsequently analyzed to identify resistance‑associated markers using a deep label‑free quantification proteomic analysis. There were >3,000 exosomal proteins identified of which, 35 were found to be differentially expressed. From this, a total of 3, namely the membrane proteins, interferon‑induced transmembrane protein 3, CD146 and CD36, were markedly upregulated in the exosomes derived from the K562IR cells, and exhibited surface localization. The upregulation of these proteins was verified in the K562IR exosomes, and also in the K562IR cells. Using flow cytometric analysis, it was possible to further demonstrate the potential of CD146 as a cell surface marker associated with imatinib resistance in K562 cells. Taken together, these results suggested that exosomes and their respective candidate surface proteins could be potential diagnostic markers of TKI drug resistance in CML therapy.
Institute of Hematology and Blood Transfusion 128 20 Prague 2 Czech Republic
Military Health Institute Military Medical Agency 160 01 Prague 6 Czech Republic
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