title: Glycometabolic adaptation mediates the insensitivity of drug-resistant K562/ADM leukaemia cells to adriamycin via the AKT-mTOR/c-Myc signalling pathway.
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.
authors.affiliation: Key Laboratory of Preclinical Study for New Drugs of Gansu, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu 730000, P.R. China.
authors.forename: Xueyan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Preclinical Study for New Drugs of Gansu, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu 730000, P.R. China.
authors.forename: Ziying
authors.initials: Z
authors.lastname: Ai
authors.affiliation: Key Laboratory of Preclinical Study for New Drugs of Gansu, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu 730000, P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Key Laboratory of Preclinical Study for New Drugs of Gansu, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu 730000, P.R. China.
authors.forename: Juan
authors.initials: J
authors.lastname: Yi
authors.affiliation: Key Laboratory of Preclinical Study for New Drugs of Gansu, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu 730000, P.R. China.
authors.forename: Zhuan
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Key Laboratory of Preclinical Study for New Drugs of Gansu, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu 730000, P.R. China.
authors.forename: Huaishun
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Preclinical Study for New Drugs of Gansu, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu 730000, P.R. China.
authors.forename: Hulai
authors.initials: H
authors.lastname: Wei
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects*; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D000903:Antibiotics, Antineoplastic; D016271:Proto-Oncogene Proteins c-myc; D004317:Doxorubicin; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D005947:Glucose