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Proteomic analysis of imatinib-resistant CML-T1 cells reveals calcium homeostasis as a potential therapeutic target

  • Authors:
    • O. Toman
    • T. Kabickova
    • O. Vit
    • R. Fiser
    • K. Machova Polakova
    • J. Zach
    • J. Linhartova
    • D. Vyoral
    • J. Petrak
  • View Affiliations / Copyright

    Affiliations: Institute of Hematology and Blood Transfusion, CZ-12820 Prague 2, Czech Republic, BIOCEV, First Faculty of Medicine, Charles University in Prague, CZ-25250 Vestec, Czech Republic, Department of Genetics and Microbiology, Faculty of Natural Sciences, Charles University in Prague, CZ-12843 Prague, Czech Republic
    Copyright: © Toman et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 1258-1268
    |
    Published online on: July 18, 2016
       https://doi.org/10.3892/or.2016.4945
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Abstract

Chronic myeloid leukemia (CML) therapy has markedly improved patient prognosis after introduction of imatinib mesylate for clinical use. However, a subset of patients develops resistance to imatinib and other tyrosine kinase inhibitors (TKIs), mainly due to point mutations in the region encoding the kinase domain of the fused BCR-ABL oncogene. To identify potential therapeutic targets in imatinib‑resistant CML cells, we derived imatinib-resistant CML-T1 human cell line clone (CML-T1/IR) by prolonged exposure to imatinib in growth media. Mutational analysis revealed that the Y235H mutation in BCR-ABL is probably the main cause of CML-T1/IR resistance to imatinib. To identify alternative therapeutic targets for selective elimination of imatinib-resistant cells, we compared the proteome profiles of CML-T1 and CML-T1/IR cells using 2-DE-MS. We identified eight differentially expressed proteins, with strongly upregulated Na+/H+ exchanger regulatory factor 1 (NHERF1) in the resistant cells, suggesting that this protein may influence cytosolic pH, Ca2+ concentration or signaling pathways such as Wnt in CML-T1/IR cells. We tested several compounds including drugs in clinical use that interfere with the aforementioned processes and tested their relative toxicity to CML-T1 and CML-T1/IR cells. Calcium channel blockers, calcium signaling antagonists and modulators of calcium homeostasis, namely thapsigargin, ionomycin, verapamil, carboxyamidotriazole and immunosuppressive drugs cyclosporine A and tacrolimus (FK-506) were selectively toxic to CML-T1/IR cells. The putative cellular targets of these compounds in CML-T1/IR cells are postulated in this study. We propose that Ca2+ homeostasis can be a potential therapeutic target in CML cells resistant to TKIs. We demonstrate that a proteomic approach may be used to characterize a TKI-resistant population of CML cells enabling future individualized treatment options for patients.
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Spandidos Publications style
Toman O, Kabickova T, Vit O, Fiser R, Polakova KM, Zach J, Linhartova J, Vyoral D and Petrak J: Proteomic analysis of imatinib-resistant CML-T1 cells reveals calcium homeostasis as a potential therapeutic target. Oncol Rep 36: 1258-1268, 2016.
APA
Toman, O., Kabickova, T., Vit, O., Fiser, R., Polakova, K.M., Zach, J. ... Petrak, J. (2016). Proteomic analysis of imatinib-resistant CML-T1 cells reveals calcium homeostasis as a potential therapeutic target. Oncology Reports, 36, 1258-1268. https://doi.org/10.3892/or.2016.4945
MLA
Toman, O., Kabickova, T., Vit, O., Fiser, R., Polakova, K. M., Zach, J., Linhartova, J., Vyoral, D., Petrak, J."Proteomic analysis of imatinib-resistant CML-T1 cells reveals calcium homeostasis as a potential therapeutic target". Oncology Reports 36.3 (2016): 1258-1268.
Chicago
Toman, O., Kabickova, T., Vit, O., Fiser, R., Polakova, K. M., Zach, J., Linhartova, J., Vyoral, D., Petrak, J."Proteomic analysis of imatinib-resistant CML-T1 cells reveals calcium homeostasis as a potential therapeutic target". Oncology Reports 36, no. 3 (2016): 1258-1268. https://doi.org/10.3892/or.2016.4945
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Spandidos Publications style
Toman O, Kabickova T, Vit O, Fiser R, Polakova KM, Zach J, Linhartova J, Vyoral D and Petrak J: Proteomic analysis of imatinib-resistant CML-T1 cells reveals calcium homeostasis as a potential therapeutic target. Oncol Rep 36: 1258-1268, 2016.
APA
Toman, O., Kabickova, T., Vit, O., Fiser, R., Polakova, K.M., Zach, J. ... Petrak, J. (2016). Proteomic analysis of imatinib-resistant CML-T1 cells reveals calcium homeostasis as a potential therapeutic target. Oncology Reports, 36, 1258-1268. https://doi.org/10.3892/or.2016.4945
MLA
Toman, O., Kabickova, T., Vit, O., Fiser, R., Polakova, K. M., Zach, J., Linhartova, J., Vyoral, D., Petrak, J."Proteomic analysis of imatinib-resistant CML-T1 cells reveals calcium homeostasis as a potential therapeutic target". Oncology Reports 36.3 (2016): 1258-1268.
Chicago
Toman, O., Kabickova, T., Vit, O., Fiser, R., Polakova, K. M., Zach, J., Linhartova, J., Vyoral, D., Petrak, J."Proteomic analysis of imatinib-resistant CML-T1 cells reveals calcium homeostasis as a potential therapeutic target". Oncology Reports 36, no. 3 (2016): 1258-1268. https://doi.org/10.3892/or.2016.4945
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