Glycometabolic adaptation mediates the insensitivity of drug-resistant K562/ADM leukaemia cells to adriamycin via the AKT-mTOR/c-Myc signalling pathway

  • Authors:
    • Xueyan Zhang
    • Ziying Ai
    • Jing Chen
    • Juan Yi
    • Zhuan Liu
    • Huaishun Zhao
    • Hulai Wei
  • View Affiliations

  • Published online on: February 10, 2017     https://doi.org/10.3892/mmr.2017.6189
  • Pages: 1869-1876
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Abstract

In human leukaemia, resistance to chemotherapy leads to treatment ineffectiveness or failure. Previous studies have indicated that cancers with increased levels of aerobic glycolysis are insensitive to numerous forms of chemotherapy and respond poorly to radiotherapy. Whether glycolysis serves a key role in drug resistance of leukaemia cells remains unclear. The present study systematically investigated aerobic glycolytic alterations and regulation in K562/adriamycin (ADM) multidrug‑resistant (MDR) and ADM‑sensitive K562 leukaemia cells in normoxia, and the association between drug resistance and improper glycometabolism. The cell proliferating activity was assessed with an MTT colorimetric assay, glycolysis, including glucose consumption, lactate export and key‑enzyme activity was determined by corresponding commercial testing kits. The expression levels of hexokinase‑II (HK‑II), lactate dehydrogenase A (LDHA), glucose transporter‑4 (GLUT‑4), AKT, p‑AKT473/308, mammalian target of rapamycin (mTOR), p‑mTOR, c‑Myc and hypoxia‑inducible factor‑1α (HIF‑1α) were analyzed by western blot or reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR). K562/ADM cells exhibited increased glucose consumption and lactate accumulation, increased lactate dehydrogenase, hexokinase and pyruvate kinase activities, and reduced phosphofructokinase activity. In addition, K562/ADM cells expressed significantly more HK‑II and GLUT‑4. Notably, inhibition of glycolysis effectively killed sensitive and resistant leukaemia cells and potently restored the sensitivity of MDR cells to the anticancer agent ADM. The AKT serine/threonine kinase (AKT)/mechanistic target of rapamycin (mTOR) signalling pathway, a crucial regulator of glycometabolic homeostasis, mediated over‑activation and upregulation of c‑Myc expression levels in K562/ADM cells, which directly stimulated glucose consumption and enhanced glycolysis. In conclusion, the present study demonstrated that MDR leukaemia cells exhibit increased aerobic glycolytic activity and that this may be responsible for resistance to chemotherapeutics in leukaemia MDR cells via activation of the AKT‑mTOR‑c‑Myc signalling pathway. Therefore, inhibition of aerobic glycolysis may be a potential therapeutic strategy to efficiently treat multidrug resistance in relapsed or refractory leukaemia and cancers.
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April-2017
Volume 15 Issue 4

Print ISSN: 1791-2997
Online ISSN:1791-3004

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Spandidos Publications style
Zhang X, Ai Z, Chen J, Yi J, Liu Z, Zhao H and Wei H: Glycometabolic adaptation mediates the insensitivity of drug-resistant K562/ADM leukaemia cells to adriamycin via the AKT-mTOR/c-Myc signalling pathway. Mol Med Rep 15: 1869-1876, 2017
APA
Zhang, X., Ai, Z., Chen, J., Yi, J., Liu, Z., Zhao, H., & Wei, H. (2017). Glycometabolic adaptation mediates the insensitivity of drug-resistant K562/ADM leukaemia cells to adriamycin via the AKT-mTOR/c-Myc signalling pathway. Molecular Medicine Reports, 15, 1869-1876. https://doi.org/10.3892/mmr.2017.6189
MLA
Zhang, X., Ai, Z., Chen, J., Yi, J., Liu, Z., Zhao, H., Wei, H."Glycometabolic adaptation mediates the insensitivity of drug-resistant K562/ADM leukaemia cells to adriamycin via the AKT-mTOR/c-Myc signalling pathway". Molecular Medicine Reports 15.4 (2017): 1869-1876.
Chicago
Zhang, X., Ai, Z., Chen, J., Yi, J., Liu, Z., Zhao, H., Wei, H."Glycometabolic adaptation mediates the insensitivity of drug-resistant K562/ADM leukaemia cells to adriamycin via the AKT-mTOR/c-Myc signalling pathway". Molecular Medicine Reports 15, no. 4 (2017): 1869-1876. https://doi.org/10.3892/mmr.2017.6189