Energy metabolism of leukemia cells: glycolysis<i>versus</i>oxidative phosphorylation

Suganuma, Kazuto; Miwa, Hiroshi; Imai, Norikazu; Shikami, Masato; Gotou, Mayuko; Goto, Mineaki; Mizuno, Shohei; Takahashi, Miyuki; Yamamoto, Hiroaki; Hiramatsu, Akihito; Wakabayashi, Motohiro; Watarai, Masaya; Hanamura, Ichiro; Imamura, Akira; Mihara, Hidetsugu; Nitta, Masakazu

doi:10.3109/10428194.2010.512966

Cited by 113 publications

(103 citation statements)

References 22 publications

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“…Regarding the energetic metabolism, our results categorize the different AML cells with NB‐4 as a glycolytic cell line, as reported in some studies,49, 50, 51 HL‐60 cells mainly dependent on glycolysis12 and KG‐1 cells displaying a predominant OXPHOS metabolism. These results not only showed that 2 closely related cell lines, NB‐4 and HL‐60, present different energetic metabolism, but also that KG‐1 cells are mainly OXPHOS dependent, as reflected by the carbon flux through mitochondria for lactate production (Figure 1).…”

Section: Discussionsupporting

confidence: 80%

Signalling mechanisms that regulate metabolic profile and autophagy of acute myeloid leukaemia cells

Pereira

Teixeira

Sampaio‐Marques

et al. 2018

J Cellular Molecular Medi

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Acute myeloid leukaemia (AML) comprises a heterogeneous group of hematologic neoplasms characterized by diverse combinations of genetic, phenotypic and clinical features representing a major challenge for the development of targeted therapies. Metabolic reprogramming, mainly driven by deregulation of the nutrient‐sensing pathways as AMPK, mTOR and PI3K/AKT, has been associated with cancer cells, including AML cells, survival and proliferation. Nevertheless, the role of these metabolic adaptations on the AML pathogenesis is still controversial. In this work, the metabolic status and the respective metabolic networks operating in different AML cells (NB‐4, HL‐60 and KG‐1) and their impact on autophagy and survival was characterized. Data show that whereas KG‐1 cells exhibited preferential mitochondrial oxidative phosphorylation metabolism with constitutive co‐activation of AMPK and mTORC1 associated with increased autophagy, NB‐4 and HL‐60 cells displayed a dependent glycolytic profile mainly associated with AKT/mTORC1 activation and low autophagy flux. Inhibition of AKT is disclosed as a promising therapeutical target in some scenarios while inhibition of AMPK and mTORC1 has no major impact on KG‐1 cells’ survival. The results highlight an exclusive metabolic profile for each tested AML cells and its impact on determination of the anti‐leukaemia efficacy and on personalized combinatory therapy with conventional and targeted agents.

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Section: Discussionsupporting

confidence: 80%

Signalling mechanisms that regulate metabolic profile and autophagy of acute myeloid leukaemia cells

Pereira

Teixeira

Sampaio‐Marques

et al. 2018

J Cellular Molecular Medi

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“…In these studies, a great deal of nucleotide alterations were detected in the D-loop region in acute myeloblastic leukemia and myelodysplastic syndrome patients, suggesting that the D-loop is a mutational hotspot in human cancer. It was found that leukemia cells utilize glycolysis more vigorously than oxidative phosphorylation in mitochondria (Gattermann, 2000;Shin et al, 2003;Grist et al, 2004;Suganuma et al, 2010). This may be caused by differences between benign and malignant hematologic disorders.…”

Section: Discussionmentioning

confidence: 99%

Complete sequence analysis of mitochondrial DNA of aplastic anemia patients

Cui¹,

Liu²,

Wang³

et al. 2012

Genet. Mol. Res.

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ABSTRACT. This study was primarily undertaken to test the hypothesis that mitochondrial DNA (mtDNA) mutations may be associated with aplastic anemia (AA). We analyzed mtDNA sequences from 15 patients with AA. The samples were obtained from bone marrow, and patients' oral epithelial cells were collected for normal tissue comparison. Total DNA was amplified by PCR after extraction, and these segments were then sent for sequencing. The results were compared with those of oral epithelial tissues as well as mtDNA sequences in the revised Cambridge Reference Sequence (rCRS) database. We detected 61 heteroplasmic mutations in 11 genes, including those encoding NADH dehydrogenase (ND)1-2 and 4-6, tRNA glutamic acid (TRNE), ribosomal RNA (RNR) 1 and 2, cytochrome c oxidase (COX1), cytochrome b (CYTB), and tRNA glycine (TRNG); mutation rates were particularly high in ND2 2131©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 11 (3): 2130-2137 (2012) Mitochondrial DNA mutation in aplastic anemia (34.4%) and ND4 (21.3%) in the patients' mtDNA genomes. The products of these genes are involved in oxidation in the respiratory chain, and a large number of homoplasmic mutations were found. Interestingly, these 162 polymorphisms were mostly in the D-loop DNA structure (54.3%), in which numerous mutations associated with leukemia and myelodysplastic syndromes are found. We conclude that functional impairment of the mitochondrial respiratory chain induced by mutation may be an important reason for hematopoietic failure in AA patients.

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“…We previously demonstrated that 2-DG treatment activates AMPK in THP-1 cells (13), which may explain the replenishment of the TCA cycle by fatty acid oxidation by carnitine palmitoyltransferase. Then, the combination of 2-DG and inhibition of AMPK by compound C potently suppressed the growth of THP-1 (Fig.…”

Section: Discussionmentioning

confidence: 99%

Leukemia cells demonstrate a different metabolic perturbation provoked by 2-deoxyglucose

et al. 2013

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Abstract. The shift in energy metabolism from oxidative phosphorylation to glycolysis can serve as a target for the inhibition of cancer growth. Here, we examined the metabolic changes induced by 2-deoxyglucose (2-DG), a glycolysis inhibitor, in leukemia cells by metabolome analysis. NB4 cells mainly utilized glucose as an energy source by glycolysis and oxidative phosphorylation in mitochondria, since metabolites in the glycolytic pathway and in the tricarboxylic acid (TCA) cycle were significantly decreased by 2-DG. In THP-1 cells, metabolites in the TCA cycle were not decreased to the same extent by 2-DG as in NB4 cells, which indicates that THP-1 utilizes energy sources other than glucose. TCA cycle metabolites in THP-1 cells may be derived from acetyl-CoA by fatty acid β-oxidation, which was supported by abundant detection of carnitine and acetylcarnitine in THP-1 cells. 2-DG treatment increased the levels of pentose phosphate pathway (PPP) metabolites and augmented the generation of NADPH by glucose-6-phosphate dehydrogenase. An increase in NADPH and upregulation of glutathione synthetase expression resulted in the increase in the reduced form of glutathione by 2-DG in NB4 cells. We demonstrated that a combination of 2-DG and inhibition of PPP by dehydroepiandrosterone (DHEA) effectively suppressed the growth of NB4 cells. The replenishment of the TCA cycle by fatty acid oxidation by carnitine palmitoyltransferase in THP-1 cells, treated by 2-DG, might be regulated by AMPK, as the combination of 2-DG and inhibition of AMPK by compound C potently suppressed the growth of THP-1 cells. Although 2-DG has been effective in preclinical and clinical studies, this treatment has not been fully explored due to concerns related to potential toxicities such as brain toxicity at high doses. We demonstrated that a combination of 2-DG and DHEA or compound C at a relatively low concentration effectively inhibits the growth of NB4 and THP-1 cells, respectively. These observations may aid in the identification of appropriate combinations of metabolic inhibitors at low concentrations which do not cause toxicities. IntroductionOne of the fundamental changes that occurs in cancer cells is the shift in energy metabolism from the generation of ATP from oxidative phosphorylation to glycolysis even in the presence of sufficient oxygen (Warburg effect) (1,2). Several agents that specifically inhibit glycolytic metabolism, such as 2-deoxy-D-glucose (2-DG), have been used as effective anticancer agents in cellular systems and in animal models (3,4). Similar to glucose, 2-DG is taken up through glucose transporters (GLUTs) and is phosphorylated by hexokinase (HK) to form 2-DG-6-phosphate (2-DG-6-P). 2-DG-6-P accumulates within the cell and is not metabolized further. Then, 2-DG-6-P induces cell growth arrest and cell death by inhibiting 2 glycolytic enzymes, HK and phosphoglucose isomerase (PGI) (5,6).Although 2-DG has been undergoing clinical trials for treatment of several types of cancers, its efficacy as a monotherapy is limited b...

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Energy metabolism of leukemia cells: glycolysisversusoxidative phosphorylation

Cited by 113 publications

References 22 publications

Signalling mechanisms that regulate metabolic profile and autophagy of acute myeloid leukaemia cells

Signalling mechanisms that regulate metabolic profile and autophagy of acute myeloid leukaemia cells

Complete sequence analysis of mitochondrial DNA of aplastic anemia patients

Leukemia cells demonstrate a different metabolic perturbation provoked by 2-deoxyglucose

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