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
Jazyk angličtina Země Řecko Médium print-electronic
Typ dokumentu časopisecké články
PubMed
33491750
DOI
10.3892/ijo.2020.5163
Knihovny.cz E-zdroje
- Klíčová slova
- chronic myeloid leukemia, imatinib mesylate, drug resistance, proteomics, exosome, tyrosine kinase inhibitor, surface marker,
- MeSH
- antigen CD146 metabolismus MeSH
- antigeny CD36 metabolismus MeSH
- apoptóza účinky léků MeSH
- bcr-abl fúzní proteiny antagonisté a inhibitory genetika MeSH
- buňky K562 MeSH
- chemorezistence MeSH
- chronická myeloidní leukemie farmakoterapie genetika patologie MeSH
- exozómy účinky léků metabolismus MeSH
- imatinib mesylát farmakologie terapeutické užití MeSH
- inhibitory proteinkinas farmakologie terapeutické užití MeSH
- lidé MeSH
- membránové proteiny metabolismus MeSH
- nádorové buněčné linie MeSH
- proteiny vázající RNA metabolismus MeSH
- viabilita buněk účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antigen CD146 MeSH
- antigeny CD36 MeSH
- bcr-abl fúzní proteiny MeSH
- BCR-ABL1 fusion protein, human MeSH Prohlížeč
- IFITM3 protein, human MeSH Prohlížeč
- imatinib mesylát MeSH
- inhibitory proteinkinas MeSH
- membránové proteiny MeSH
- proteiny vázající RNA 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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