Glucose, not glutamine, is the dominant energy source required for proliferation and survival of head and neck squamous carcinoma cells

Sandulache, Vlad C.; Ow, Thomas J.; Pickering, Curtis R.; Frederick, Mitchell J.; Zhou, Ge; Fokt, Izabela; Davis-Malesevich, Melinda; Priebe, Waldemar; Myers, Jeffrey N.

doi:10.1002/cncr.25868

Cited by 120 publications

(143 citation statements)

References 51 publications

(62 reference statements)

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“…To a certain extent, our results also confirm the observation that glucose, not glutamine, is the dominant energy source required for the proliferation and survival of HN-SCC cells. 22 On the other hand, the induction of SLC1A5 by 10058-F4 is consistent with the results of other authors who showed an elevated expression of this transporter as a response to c-MYC inhibition in human P-493 B lymphoma and PC3 prostate cancer cells. 12,23 However, the mechanism which leads to the decrease in ammonia production is elusive since it cannot be explained by changes in the gene expression level alone.…”

Section: Discussionsupporting

confidence: 92%

“…21 A better understanding of tumor metabolism in HNSCCs may provide new therapeutic strategies for the treatment of this type of cancer. The data on the regulation of energetic metabolism in HNSCCs, although limited, 22 suggests that head and neck cancer cell proliferation depends on glucose and glutamine metabolism. The aim of this study was to evaluate the influence of small molecules -inhibitors of specific regulators of both c-MYC inhibitor (10058-F4) and HIF-1 inhibitor (KG-548) pathways -on the proliferation and metabolism of the hypopharyngeal carcinoma FaDu cells.…”

mentioning

confidence: 99%

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The inhibition of c-MYC transcription factor modulates the expression of glycolytic and glutaminolytic enzymes in FaDu hypopharyngeal carcinoma cells

Kleszcz¹,

Paluszczak²,

Krajka‐Kuźniak³

et al. 2018

Adv Clin Exp Med

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Background. Cancer cells are dependent on aerobic glycolysis for energy production and increased glutamine consumption. HIF-1α and c-MYC transcription factors regulate the expression of glycolytic and glutaminolytic genes. Their activity may be repressed by SIRT6. Head and neck carcinomas show frequent activation of c-MYC function and SIRT6 down-regulation, which contributes to a strong dependence on glucose and glutamine availability.

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Section: Discussionsupporting

confidence: 92%

mentioning

confidence: 99%

The inhibition of c-MYC transcription factor modulates the expression of glycolytic and glutaminolytic enzymes in FaDu hypopharyngeal carcinoma cells

Kleszcz¹,

Paluszczak²,

Krajka‐Kuźniak³

et al. 2018

Adv Clin Exp Med

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“…2-DG treatment increased the PPP metabolites in both cell lines. After entering the cell, 2-DG is phosphorylated by hexokinase to form 2-DG-6-phosphate, which cannot be further metabolized, and its accumulation leads to inhibition of the glycolytic pathway and shunting through the PPP (5,14,15). This PPP flux augments the generation of NADPH by glucose-6-phosphate dehydrogenase (G-6-PDH).…”

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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“…Since then, several reports have shown that glutamine may be used as the energy fuel for cancer cells (42)(43)(44)(45). In contrast to glucose, glutamine as an energy fuel is only observed in a few cancer cell lines (27) and plays an important role in compensating for the shortage of glucose in some cases.…”

Section: Certain Cancer Cells May Use Glutamine As Energy Fuelmentioning

confidence: 99%

“…Lactate is converted to pyruvate by LDH-B and then enters the mitochondria for OXPHOS to generate ATP (3,14,22,(25)(26)(27)(28). Metabolic symbiosis is not cancer-specific.…”

Section: Glycolysis Versus Oxphosmentioning

confidence: 99%

Energy metabolism of cancer: Glycolysis versus oxidative phosphorylation (Review)

2012

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Abstract. Metabolic activities in normal cells rely primarily on mitochondrial oxidative phosphorylation (OXPHOS) to generate ATP for energy. Unlike in normal cells, glycolysis is enhanced and OXPHOS capacity is reduced in various cancer cells. It has long been believed that the glycolytic phenotype in cancer is due to a permanent impairment of mitochondrial OXPHOS, as proposed by Otto Warburg. This view is challenged by recent investigations which find that the function of mitochondrial OXPHOS in most cancers is intact. Aerobic glycolysis in many cancers is the combined result of various factors such as oncogenes, tumor suppressors, a hypoxic microenvironment, mtDNA mutations, genetic background and others. Understanding the features and complexity of the cancer energy metabolism will help to develop new approaches in early diagnosis and effectively target therapy of cancer.

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Glucose, not glutamine, is the dominant energy source required for proliferation and survival of head and neck squamous carcinoma cells

Cited by 120 publications

References 51 publications

The inhibition of c-MYC transcription factor modulates the expression of glycolytic and glutaminolytic enzymes in FaDu hypopharyngeal carcinoma cells

The inhibition of c-MYC transcription factor modulates the expression of glycolytic and glutaminolytic enzymes in FaDu hypopharyngeal carcinoma cells

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

Energy metabolism of cancer: Glycolysis versus oxidative phosphorylation (Review)

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