Lactate downregulates the glycolytic enzymes hexokinase and phosphofructokinase in diverse tissues from mice

Leite, Tiago Costa; Coelho, Raquel Fernandes; Silva, Daniel da; Coelho, Wagner Santos; Marinho-Carvalho, Monica M.; Sola‐Penna, Mauro

doi:10.1016/j.febslet.2010.11.009

Cited by 137 publications

(117 citation statements)

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“…PFKP (encoded by PFKP gene) is a platelet isoform of phosphofructokinase that catalyzes the irreversible conversion of fructose-6-phosphate to fructose-1,6-bisphosphate and is a key regulator enzyme in glycolysis [26], while DGKH (encoded by DGKH gene) is a member of the diacylglycerol kinase enzyme family of proteins that are involved in regulating the intracellular concentrations of diacylglycerol and phosphatidic acid [27]. Roles of DGKH and PFKP in lung cancer have not been fully discussed.…”

Section: Discussionmentioning

confidence: 99%

Identification of lung cancer oncogenes based on the mRNA expression and single nucleotide polymorphism profile data

Y¹,

Mei²,

Yq³

et al. 2015

neo

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This study aimed to identify the oncogenes associated with lung cancer based on the mRNA and single nucleotide polymorphism (SNP) profile data. The mRNA expression profile data of GSE43458 (80 cancer and 30 normal samples) and SNP profile data of GSE33355 (61 pairs of lung cancer samples and control samples) were downloaded from Gene Expression Omnibus database. Common genes between the mRNA profile and SNP profile were identified as the lung cancer oncogenes. Risk subpathways of the selected oncogenes with the SNP locus were analyzed using the iSubpathwayMiner package in R. Moreover, protein-protein interaction (PPI) network of the oncogenes was constructed using the HPRD database and then visualized using the Cytoscape. Totally, 3004 DEGs (1105 up-regulated and 1899 down-regulated) and 125 significant SNPs closely related to 174 genes in the lung cancer samples were identified. Also, 39 common genes, like PFKP (phosphofructokinase, platelet) and DGKH-rs11616202 (diacylglycerol kinase, eta) that enriched in sub-pathways such as galactose metabolism, fructose and mannose metabolism, and pentose phosphate pathway, were identified as the lung cancer oncogenes. Besides, PIK3R1 (phosphoinositide-3-kinase, regulatory subunit 1), RORA (RAR-related orphan receptor A), MAGI3 (membrane associated guanylate kinase, WW and PDZ domain containing 3), PTPRM (protein tyrosine phosphatase, receptor type, M), and BMP6 (bone morphogenetic protein 6) were the hub genes in PPI network. Our study suggested that PFKP and DGKH that enriched in galactose metabolism, fructose and mannose metabolism pathway, as well as PIK3R1, RORA, and MAGI3, may be the lung cancer oncogenes. Key words: lung cancer, single nucleotide polymorphism (SNP), function analysis, differentially expressed gene, oncogenesAbbreviations: SNP -single nucleotide polymorphism; PPI -proteinprotein interaction; DEGs -differentially expressed genes Lung cancer is one of the most common malignancies with an increasing morbidity and mortality and is a worldwide leading cause of cancer-related death with a 5-year survival rate from 13% to 15% [1]. Mechanism of lung cancer is complicate, mainly due to the late diagnosis and lack of effective treatment [2]. Therefore, underlying the molecular profiles of lung cancer as well as elucidating the roles of oncogenes and tumor suppressors in the development of this malignancy is expected to identify the molecular targets for lung cancer prediction and treatment.Previous studies have demonstrated that environmental factors like smoking and air pollution, and gene polymorphisms were the main factors contributing to the lung cancer progression and metastasis [3]. Chemical constituents in tobacco smoke including compounds of the carcinogenic polycyclic type were the carcinogen for lung cancer [4]. A previous study reveals that mutations of the tumor suppressor genes are a main reason for lung cancer progression, such as the prevalence of p53 mutational patterns G to T transversions is 30% and p53 mutations in lung cancer can be attribu...

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Section: Discussionmentioning

confidence: 99%

Identification of lung cancer oncogenes based on the mRNA expression and single nucleotide polymorphism profile data

Y¹,

Mei²,

Yq³

et al. 2015

neo

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“…The association of glycolytic enzymes to these intracellular ultrastructures is an important mechanism of regulation of glucose consumption, determining if it will be completely oxidized, fermented, or used as carbon source for biosynthesis (17,19,20,22,36,(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53). The more associated the enzymes are, the less oxidized glucose is, being preferentially fermented and used to biosynthesis.…”

Section: Discussionmentioning

confidence: 99%

“…Both HK and PFK are subjected to multiple regulatory mechanisms, including allosteric regulation by metabolites and control by hormones (14,15,(18)(19)(20)(21)(22)(23). Moreover, these two enzymes, as others from glycolysis, are able to reversibly associate to intracellular ultrastructures, such as the mitochondria for HK and actin filaments (f-actin) for PFK, as part of their regulatory mechanism (15,17).…”

Section: Introductionmentioning

confidence: 99%

Metformin reverses hexokinase and phosphofructokinase downregulation and intracellular distribution in the heart of diabetic mice

Silva¹,

Ausina²,

Alencar³

et al. 2012

IUBMB Life

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SummaryDiabetes mellitus is characterized by hyperglycemia and its associated complications, including cardiomyopathy. Metformin, in addition to lowering blood glucose levels, provides cardioprotection for diabetic subjects. Glycolysis is essential to cardiac metabolism and its reduction may contribute to diabetic cardiomyopathy. Hexokinase (HK) and phosphofructokinase (PFK), rate-limiting enzymes of glycolysis, are downregulated in cardiac muscle from diabetic subjects, playing a central role on the decreased glucose utilization in the heart of diabetic subjects. Thus, the aim of this study was to determine whether metformin modulates heart HK and PFK from diabetic mice. Diabetes was induced by streptozotocin injection on male Swiss mice, which were treated for three consecutive days with 250 mg/kg metformin before evaluating HK and PFK activity, expression, and intracellular distribution on the heart of these subjects. We show that metformin abrogates the downregulation of HK and PFK in the heart of streptozotocin-induced diabetic mice. This effect is not correlated to alteration on the enzymes' transcription and expression. However, the intracellular distribution of both enzymes is altered in diabetic hearts that show increased activity of the soluble fraction when compared to the particulate fraction. Moreover, this pattern is reversed upon the treatment with metformin, which is correlated with the effects of the drug on the enzymes activity. Altogether, our results support evidences that metformin alter the intracellular localization of HK and PFK augmenting glucose utilization by diabetic hearts and, thus, conferring cardiac protection to diabetic subjects.

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“…After the incubation period, the muscles were homogenized in the same buffer to measure hexokinase (HK) activity. HK activity was measured in a medium containing 50 mM Tris-HCl (pH 7.4), 5 mM MgCl 2 , 1 mM glucose, 1 mM ATP, 0.2 mM NADP, and 1 U/ml glucose 6-phosphate dehydrogenase, as previously described (Leite et al 2011). For enzymatic analysis, NADP reduction was determined by the change in absorbance at 340 nm in a microplate reader (Victor X4, PerkinElmer, Norwalk, CT).…”

Section: Glucose Consumption and Hexokinase Activity In Isolated Skelmentioning

confidence: 99%

Nandrolone decanoate inhibits gluconeogenesis and decreases fasting glucose in Wistar male rats

Frankenfeld¹,

Oliveira²,

Ignacio³

et al. 2014

Journal of Endocrinology

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The use of anabolic-androgenic steroids to improve physical performance or appearance has increased notably. The doses used are 10-to 100-fold higher than the therapeutic dose (TD), and this abuse can cause several side effects. Glucose metabolism is significantly affected by anabolic-androgenic steroid abuse, but studies about glycemic regulation during fasting are scarce. There are some evidences showing that testosterone can antagonize glucocorticoids action, which are crucial to glucose production during fasting. Thus, the aim of this study was to determine the impact of supraphysiological doses (SDs) of nandrolone decanoate (DECA) on rat glucose metabolism during fasting. Male Wistar rats were treated with i.m. injections of vehicle, a low TD (0.016 mg/100 g b.w.-TD group) or a high SD (1 mg/100 g b.w.-SD group) of DECA, once a week for 8 weeks. After 12 h fasting, we evaluated glucose and pyruvate tolerance tests, liver glycogen content, serum levels of gluconeogenic substrates, insulin and corticosterone, glucose uptake and hexokinase (HK) activity in skeletal muscle, and the adrenal catecholamine content. SD group had increased serum insulin levels and a blunted response to insulin regarding glucose uptake in skeletal muscle. Fasting serum glucose decreased significantly in SD group, as well as the pyruvate tolerance test and liver glycogen content. Moreover, serum levels of glycerol were increased in SD group. Our data indicate that SDs of DECA exert effects on different regulatory points of glucose metabolism, resulting in defective gluconeogenesis and decreased skeletal muscle glucose uptake in response to insulin.

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Lactate downregulates the glycolytic enzymes hexokinase and phosphofructokinase in diverse tissues from mice

Cited by 137 publications

References 31 publications

Identification of lung cancer oncogenes based on the mRNA expression and single nucleotide polymorphism profile data

Identification of lung cancer oncogenes based on the mRNA expression and single nucleotide polymorphism profile data

Metformin reverses hexokinase and phosphofructokinase downregulation and intracellular distribution in the heart of diabetic mice

Nandrolone decanoate inhibits gluconeogenesis and decreases fasting glucose in Wistar male rats

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