Targeting glycometabolic reprogramming to restore the sensitivity of leukemia drug-resistant K562/ADM cells to adriamycin
2018
Zhang, Xueyan | Chen, Jing | Ai, Ziying | Zhang, Zhewen | Lin, Li | Wei, Hulai
Mounting studies have confirmed that cancer cells reprogram their metabolism during early carcinogenesis to develop many other hallmarks, and demonstrated a relationship between aerobic glycolysis and the occurrence of drug resistance. However, the molecular mechanisms and role in tumor drug resistance of aerobic glycolysis remain unclear.We analyzed differentially expressed genes (DEGs) at the RNA level between the multi-drug resistance (MDR) leukemia cell line K562/adriamycin (ADM) and its parental, drug-sensitive K562 cell line. Clustering and enrichment analysis of DEGs was performed. Oxamate, a lactic dehydrogenase inhibitor were used to assess the effect of glycolysis inhibition on ADM susceptibility and the expression of the enriched DEGs in K562/ADM cells.A total of 1742 DEGs were detected between the K562/ADM and K562 cell lines. The differential expression of unigenes encoding enzymes involved in glycometabolism signifies that there was a greater aerobic glycolysis flux in K562/ADM cells. The PI3K-AKT signaling pathway, which is related to glucose metabolism, showed representative differential enrichment and up-regulation in K562/ADM cells. Oxamate improved and re-sensitized the therapeutic effect of ADM in ADM-resistant cells by inhibiting aerobic glycolysis either directly or indirectly by down-regulation of the AKT-mTOR pathway.Our findings suggest that ADM resistance mediated by the increase of aerobic glycolysis, which related to the over-activation of the AKT-mTOR-c-Myc pathway in MDR leukemia cells. Inhibition of aerobic glycolysis and down-regulation of signaling pathways involved in aerobic glycolysis represent a potential chemotherapeutic strategy for sensitizing leukemic cells and thereby overcoming MDR.
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