Showing papers on "Glycolysis published in 2019"
TL;DR: The Warburg effect is the central contributor to the cancer progression machinery and synergistically favors tumor progression and resistance to certain antitumor therapies, and compromises antitumors immunity.
Abstract: In the early 1920s, Warburg published experimental data on the enhanced conversion of glucose to pyruvate (followed by lactate formation) even in the presence of abundant oxygen (aerobic glycolysis, Warburg effect). He attributed this metabolic trait to a respiratory injury and considered this a universal metabolic alteration in carcinogenesis. This interpretation of the data was questioned since the early 1950s. Realistic causative mechanisms and consequences of the Warburg effect were described only during the past 15 years and are summarized in this article. There is clear evidence that mitochondria are not defective in most cancers. Aerobic glycolysis, a key metabolic feature of the Warburg phenotype, is caused by active metabolic reprogramming required to support sustained cancer cell proliferation and malignant progression. This metabolic switch is directed by altered growth factor signaling, hypoxic or normoxic activation of HIF-1α- transcription, oncogene activation or loss-of-function of suppressor genes, and is implemented in the hostile tumor microenvironment. The 'selfish' reprogramming includes (a) overexpression of glucose transporters and of key glycolytic enzymes, and an accelerated glycolytic flux with subsequent accumulation and diversion of glycolytic intermediates for cancer biomass synthesis, (b) high-speed ATP production that meets the energy demand, and (c) accumulation of lactate which drives tumor progression and largely contributes to tumor acidosis, which in turn synergistically favors tumor progression and resistance to certain antitumor therapies, and compromises antitumor immunity. Altogether, the Warburg effect is the central contributor to the cancer progression machinery.
382 citations
TL;DR: Findings revealing that a novel HIF-1-activating factor enhances the antioxidant capacity and resultant radioresistance of cancer cells though reprogramming of the glucose metabolic pathway are summarized.
Abstract: Normal cells produce adenosine 5′-triphosphate (ATP) mainly through mitochondrial oxidative phosphorylation (OXPHOS) when oxygen is available. Most cancer cells, on the other hand, are known to produce energy predominantly through accelerated glycolysis, followed by lactic acid fermentation even under normoxic conditions. This metabolic phenomenon, known as aerobic glycolysis or the Warburg effect, is less efficient compared with OXPHOS, from the viewpoint of the amount of ATP produced from one molecule of glucose. However, it and its accompanying pathway, the pentose phosphate pathway (PPP), have been reported to provide advantages for cancer cells by producing various metabolites essential for proliferation, malignant progression, and chemo/radioresistance. Here, focusing on a master transcriptional regulator of adaptive responses to hypoxia, the hypoxia-inducible factor 1 (HIF-1), we review the accumulated knowledge on the molecular basis and functions of the Warburg effect and its accompanying pathways. In addition, we summarize our own findings revealing that a novel HIF-1-activating factor enhances the antioxidant capacity and resultant radioresistance of cancer cells though reprogramming of the glucose metabolic pathway.
261 citations
TL;DR: It is proposed that lactate/SLC5A12-induced metabolic reprogramming is a distinctive feature of lymphoid synovitis in rheumatoid arthritis patients and a potential therapeutic target in chronic inflammatory disorders.
238 citations
TL;DR: Oral administration of high-fructose corn syrup is investigated in adenomatous polyposis coli mutant mice, which are predisposed to develop intestinal tumors, to support the hypothesis that the combination of dietary glucose and fructose, even at a moderate dose, can enhance tumorigenesis.
Abstract: Excessive consumption of beverages sweetened with high-fructose corn syrup (HFCS) is associated with obesity and with an increased risk of colorectal cancer. Whether HFCS contributes directly to tumorigenesis is unclear. We investigated the effects of daily oral administration of HFCS in adenomatous polyposis coli (APC) mutant mice, which are predisposed to develop intestinal tumors. The HFCS-treated mice showed a substantial increase in tumor size and tumor grade in the absence of obesity and metabolic syndrome. HFCS increased the concentrations of fructose and glucose in the intestinal lumen and serum, respectively, and the tumors transported both sugars. Within the tumors, fructose was converted to fructose-1-phosphate, leading to activation of glycolysis and increased synthesis of fatty acids that support tumor growth. These mouse studies support the hypothesis that the combination of dietary glucose and fructose, even at a moderate dose, can enhance tumorigenesis.
207 citations
TL;DR: The metabolome of activated macrophages during efferocytosis is reported to reveal an interleukin-10 (IL-10) cytokine escalation that was independent of glycolysis yet bolstered by apoptotic cell fatty acids and mitochondrial β-oxidation, the electron transport chain, and heightened coenzyme NAD+.
200 citations
TL;DR: Characterizing changes in beta-cell metabolism in hyperglycemia which may contribute to insufficient insulin secretion in type 2 diabetes and, using a multi-omics approach, find that mitochondrial metabolism is perturbed are found.
Abstract: Diabetes is a global health problem caused primarily by the inability of pancreatic β-cells to secrete adequate levels of insulin. The molecular mechanisms underlying the progressive failure of β-cells to respond to glucose in type-2 diabetes remain unresolved. Using a combination of transcriptomics and proteomics, we find significant dysregulation of major metabolic pathways in islets of diabetic βV59M mice, a non-obese, eulipidaemic diabetes model. Multiple genes/proteins involved in glycolysis/gluconeogenesis are upregulated, whereas those involved in oxidative phosphorylation are downregulated. In isolated islets, glucose-induced increases in NADH and ATP are impaired and both oxidative and glycolytic glucose metabolism are reduced. INS-1 β-cells cultured chronically at high glucose show similar changes in protein expression and reduced glucose-stimulated oxygen consumption: targeted metabolomics reveals impaired metabolism. These data indicate hyperglycaemia induces metabolic changes in β-cells that markedly reduce mitochondrial metabolism and ATP synthesis. We propose this underlies the progressive failure of β-cells in diabetes.
190 citations
TL;DR: It is shown that non-transformed mouse fibroblasts also increase oxidative phosphorylation (OXPHOS) by nearly two-fold and mitochondrial coupling efficiency by ~30% during proliferation, both increases are supported by mitochondrial fusion.
Abstract: Proliferating cells often have increased glucose consumption and lactate excretion relative to the same cells in the quiescent state, a phenomenon known as the Warburg effect. Despite an increase in glycolysis, however, here we show that non-transformed mouse fibroblasts also increase oxidative phosphorylation (OXPHOS) by nearly two-fold and mitochondrial coupling efficiency by ~30% during proliferation. Both increases are supported by mitochondrial fusion. Impairing mitochondrial fusion by knocking down mitofusion-2 (Mfn2) was sufficient to attenuate proliferation, while overexpressing Mfn2 increased proliferation. Interestingly, impairing mitochondrial fusion decreased OXPHOS but did not deplete ATP levels. Instead, inhibition caused cells to transition from excreting aspartate to consuming it. Transforming fibroblasts with the Ras oncogene induced mitochondrial biogenesis, which further elevated OXPHOS. Notably, transformed fibroblasts continued to have elongated mitochondria and their proliferation remained sensitive to inhibition of Mfn2. Our results suggest that cell proliferation requires increased OXPHOS as supported by mitochondrial fusion.
182 citations
TL;DR: In mice exposed to 24-h feeding/fasting cycles, metformin impaired tumor growth only when administered during fasting-induced hypoglycemia, and was mediated by glycogen synthase kinase 3β activation downstream of PP2A, leading to a decline in the pro-survival protein MCL-1, and cell death.
176 citations
TL;DR: The findings show that 4-OI has anti-inflammatory effects by targeting GAPDH to decrease aerobic glycolysis in macrophages and protects against lipopolysaccharide-induced lethality in vivo and inhibits cytokine release.
Abstract: Activated macrophages switch from oxidative phosphorylation to aerobic glycolysis, similar to the Warburg effect, presenting a potential therapeutic target in inflammatory disease. The endogenous metabolite itaconate has been reported to regulate macrophage function, but its precise mechanism is not clear. Here, we show that 4-octyl itaconate (4-OI, a cell-permeable itaconate derivative) directly alkylates cysteine residue 22 on the glycolytic enzyme GAPDH and decreases its enzyme activity. Glycolytic flux analysis by U13C glucose tracing provides evidence that 4-OI blocks glycolytic flux at GAPDH. 4-OI thereby downregulates aerobic glycolysis in activated macrophages, which is required for its anti-inflammatory effects. The anti-inflammatory effects of 4-OI are replicated by heptelidic acid, 2-DG and reversed by increasing wild-type (but not C22A mutant) GAPDH expression. 4-OI protects against lipopolysaccharide-induced lethality in vivo and inhibits cytokine release. These findings show that 4-OI has anti-inflammatory effects by targeting GAPDH to decrease aerobic glycolysis in macrophages. Redirection of the TCA cycle intermediate aconitate to itaconate production has anti-inflammatory effects. Here the authors show that the itaconate derivative 4-octyl-itaconate is anti-inflammatory partly as a result of inhibiting GAPDH enzymatic activity and thereby glycolysis in macrophages.
168 citations
TL;DR: Targeting a few metabolic enzymes also periodically translocate to the nucleus and oversee cell cycle regulators or oncogene expression could increase the response to CDK inhibitors (CKIs).
160 citations
TL;DR: Having a common glucose sensor couples complementary regulatory mechanisms into a tightly regulated and stable glucose homeostatic network.
Abstract: It is hypothesized that glucokinase (GCK) is the glucose sensor not only for regulation of insulin release by pancreatic β-cells, but also for the rest of the cells that contribute to glucose homeostasis in mammals. This includes other cells in endocrine pancreas (α- and δ-cells), adrenal gland, glucose sensitive neurons, entero-endocrine cells, and cells in the anterior pituitary. Glucose transport is by facilitated diffusion and is not rate limiting. Once inside, glucose is phosphorylated to glucose-6-phosphate by GCK in a reaction that is dependent on glucose throughout the physiological range of concentrations, is irreversible, and not product inhibited. High glycerol phosphate shuttle, pyruvate dehydrogenase, and pyruvate carboxylase activities, combined with low pentose-P shunt, lactate dehydrogenase, plasma membrane monocarboxylate transport, and glycogen synthase activities constrain glucose-6-phosphate to being metabolized through glycolysis. Under these conditions, glycolysis produces mostly pyruvate and little lactate. Pyruvate either enters the citric acid cycle through pyruvate dehydrogenase or is carboxylated by pyruvate carboxylase. Reducing equivalents from glycolysis enter oxidative phosphorylation through both the glycerol phosphate shuttle and citric acid cycle. Raising glucose concentration increases intramitochondrial [NADH]/[NAD+] and thereby the energy state ([ATP]/[ADP][Pi]), decreasing [Mg2+ADP] and [AMP]. [Mg2+ADP] acts through control of KATP channel conductance, whereas [AMP] acts through regulation of AMP-dependent protein kinase. Specific roles of different cell types are determined by the diverse molecular mechanisms used to couple energy state to cell specific responses. Having a common glucose sensor couples complementary regulatory mechanisms into a tightly regulated and stable glucose homeostatic network.
TL;DR: The function and regulation of key gluconeogenic enzymes and new therapeutic opportunities are reviewed.
Abstract: Cancer cells display a high rate of glycolysis in the presence of oxygen to promote proliferation. Gluconeogenesis, the reverse pathway of glycolysis, can antagonize aerobic glycolysis in cancer via three key enzymes – phosphoenolpyruvate carboxykinase (PEPCK), fructose-1,6-bisphosphatase (FBPase), and glucose-6-phosphatase (G6Pase). Recent studies have revealed that, in addition to metabolic regulation, these enzymes also play a role in signaling, proliferation, and the cancer stem cell (CSC) tumor phenotype. Multifaceted regulation of PEPCK, FBPase, and G6Pase through transcription, epigenetics, post-translational modification, and enzymatic activity is observed in different cancers. We review here the function and regulation of key gluconeogenic enzymes and new therapeutic opportunities.
TL;DR: Light is shed on the current knowledge of cancer cell gluconeogenesis and its role in metabolic reprogramming, cancer cell plasticity, and tumor growth and fructose-1,6-bisphosphatase 1, a downstream gluc oneogenesis enzyme, inhibits glycolysis and tumorgrowth.
TL;DR: It is concluded that upon glycolytic suppression in multiple types of tumor cells, intracellular energy metabolism is reprogrammed toward mitochondrial OXPHOS in an autophagy-dependent manner to ensure cellular survival.
Abstract: Most cancer cells rely on glycolysis to generate ATP, even when oxygen is available. However, merely inhibiting the glycolysis is insufficient for the eradication of cancer cells. One main reason for this is that cancer cells have the potential to adapt their metabolism to their environmental conditions. In this study, we investigated how cancer cells modify their intracellular metabolism when glycolysis is suppressed, using PANC-1 pancreatic cancer cells and two other solid tumor cell lines, A549 and HeLa. Our study revealed that glycolytically suppressed cells upregulated mitochondrial function and relied on oxidative phosphorylation (OXPHOS) to obtain the ATP necessary for their survival. Dynamic changes in intracellular metabolic profiles were also observed, reflected by the reduced levels of TCA cycle intermediates and elevated levels of most amino acids. Glutamine and glutamate were important for this metabolic reprogramming, as these were largely consumed by influx into the TCA cycle when the glycolytic pathway was suppressed. During the reprogramming process, activated autophagy was involved in modulating mitochondrial function. We conclude that upon glycolytic suppression in multiple types of tumor cells, intracellular energy metabolism is reprogrammed toward mitochondrial OXPHOS in an autophagy-dependent manner to ensure cellular survival.
TL;DR: It is found that enhancing PGK1 activity and increasing glycolysis may slow neurodegeneration in PD and a reduced frequency of PD diagnoses in individuals taking TZ and related drugs is found.
Abstract: Parkinson's disease (PD) is a common neurodegenerative disease that lacks therapies to prevent progressive neurodegeneration. Impaired energy metabolism and reduced ATP levels are common features of PD. Previous studies revealed that terazosin (TZ) enhances the activity of phosphoglycerate kinase 1 (PGK1), thereby stimulating glycolysis and increasing cellular ATP levels. Therefore, we asked whether enhancement of PGK1 activity would change the course of PD. In toxin-induced and genetic PD models in mice, rats, flies, and induced pluripotent stem cells, TZ increased brain ATP levels and slowed or prevented neuron loss. The drug increased dopamine levels and partially restored motor function. Because TZ is prescribed clinically, we also interrogated 2 distinct human databases. We found slower disease progression, decreased PD-related complications, and a reduced frequency of PD diagnoses in individuals taking TZ and related drugs. These findings suggest that enhancing PGK1 activity and increasing glycolysis may slow neurodegeneration in PD.
TL;DR: Synthetic lethal combination therapies are essential to attack the liabilities of the Warburg metabolism for therapeutic benefit and may promote or suppress tumor metastasis.
Abstract: The Warburg effect is prevalent in human cancer. Accordingly, most cancer cells display highly elevated glycolysis without proportionally increasing pyruvate oxidation. The metastatic process imposes strong selective pressure on cancer cells, and metastasizing cancer cells experience heightened oxidative stress. By constraining mitochondrial oxidative metabolism, the Warburg effect helps cancer cells to minimize oxidative stress, thereby facilitating metastatic dissemination. The PGC1α transcriptional coactivator is a central coordinator of oxidative metabolism. While promoting oxidative metabolism and reversing the Warburg effect, PGC1α critically activates antioxidant genes and protects cells against oxidative damage. Therefore, depending on the context, PGC1α may promote or suppress tumor metastasis. Cancer cells generally retain metabolic flexibility and can resist antiglycolysis treatment by undergoing metabolic reprogramming. Synthetic lethal combination therapies are thus essential to attack the liabilities of the Warburg metabolism for therapeutic benefit.
TL;DR: It is reported that the SNO-CoA–AKR1A1 system is highly expressed in renal proximal tubules, where it transduces the activity of eNOS in reprogramming intermediary metabolism, thereby protecting kidneys against acute kidney injury.
Abstract: Endothelial nitric oxide synthase (eNOS) is protective against kidney injury, but the molecular mechanisms of this protection are poorly understood1,2. Nitric oxide-based cellular signalling is generally mediated by protein S-nitrosylation, the oxidative modification of Cys residues to form S-nitrosothiols (SNOs). S-nitrosylation regulates proteins in all functional classes, and is controlled by enzymatic machinery that includes S-nitrosylases and denitrosylases, which add and remove SNO from proteins, respectively3,4. In Saccharomyces cerevisiae, the classic metabolic intermediate co-enzyme A (CoA) serves as an endogenous source of SNOs through its conjugation with nitric oxide to form S-nitroso-CoA (SNO-CoA), and S-nitrosylation of proteins by SNO-CoA is governed by its cognate denitrosylase, SNO-CoA reductase (SCoR)5. Mammals possess a functional homologue of yeast SCoR, an aldo-keto reductase family member (AKR1A1)5 with an unknown physiological role. Here we report that the SNO-CoA-AKR1A1 system is highly expressed in renal proximal tubules, where it transduces the activity of eNOS in reprogramming intermediary metabolism, thereby protecting kidneys against acute kidney injury. Specifically, deletion of Akr1a1 in mice to reduce SCoR activity increased protein S-nitrosylation, protected against acute kidney injury and improved survival, whereas this protection was lost when Enos (also known as Nos3) was also deleted. Metabolic profiling coupled with unbiased mass spectrometry-based SNO-protein identification revealed that protection by the SNO-CoA-SCoR system is mediated by inhibitory S-nitrosylation of pyruvate kinase M2 (PKM2) through a novel locus of regulation, thereby balancing fuel utilization (through glycolysis) with redox protection (through the pentose phosphate shunt). Targeted deletion of PKM2 from mouse proximal tubules recapitulated precisely the protective and mechanistic effects of S-nitrosylation in Akr1a1-/- mice, whereas Cys-mutant PKM2, which is refractory to S-nitrosylation, negated SNO-CoA bioactivity. Our results identify a physiological function of the SNO-CoA-SCoR system in mammals, describe new regulation of renal metabolism and of PKM2 in differentiated tissues, and offer a novel perspective on kidney injury with therapeutic implications.
TL;DR: Current knowledge on the implications of NAD metabolism in metabolic diseases is summarized and the outcomes of recent human clinical trials are discussed to investigate the safety, pharmacokinetics, and efficacy against metabolic disorders such as glucose intolerance.
Abstract: Nicotinamide adenine dinucleotide (NAD) is an important coenzyme that participates in various energy metabolism pathways, including glycolysis, β-oxidation, and oxidative phosphorylation. Besides, it is a required cofactor for post-translational modifications such as ADP-ribosylation and deacetylation by poly (ADP-ribose) polymerases (PARPs) and sirtuins, respectively. Thus, NAD regulates energy metabolism, DNA damage repair, gene expression, and stress response through these enzymes. Numerous studies have shown that NAD levels decrease with aging and under disturbed nutrient conditions, such as obesity. Additionally, a decline in NAD levels is closely related to the development of various metabolic disorders, including diabetes and fatty liver disease. In addition, many studies have revealed that administration of NAD precursors, such as nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), efficiently increase NAD levels in various tissues and prevent such metabolic diseases. These NAD precursors are contained in natural foods, such as cow milk, vegetables, and meats. Therefore, altered NAD metabolism can be a practical target for nutritional intervention. Recently, several human clinical trials using NAD precursors have been conducted to investigate the safety, pharmacokinetics, and efficacy against metabolic disorders such as glucose intolerance. In this review, we summarize current knowledge on the implications of NAD metabolism in metabolic diseases and discuss the outcomes of recent human clinical trials.
TL;DR: It is demonstrated that lipopolysaccharide-activated human peripheral blood monocyte-derived macrophages fail to undergo metabolic reprogramming towards glycolysis, but rely on oxidative phosphorylation for the generation of ATP.
Abstract: Macrophages adopt different phenotypes in response to microenvironmental changes, which can be principally classified into inflammatory and anti-inflammatory states. Inflammatory activation of macrophages has been linked with metabolic reprogramming from oxidative phosphorylation to aerobic glycolysis. In contrast to mouse macrophages, little information is available on the link between metabolism and inflammation in human macrophages. In the current report it is demonstrated that lipopolysaccharide (LPS)-activated human peripheral blood monocyte-derived macrophages (hMDMs) fail to undergo metabolic reprogramming towards glycolysis, but rely on oxidative phosphorylation for the generation of ATP. By contrast, activation by LPS led to an increased extracellular acidification rate (glycolysis) and decreased oxygen consumption rate (oxidative phosphorylation) in mouse bone marrow-derived macrophages (mBMDMs). Mitochondrial bioenergetics after LPS stimulation in human macrophages was unchanged, but was markedly impaired in mouse macrophages. Furthermore, treatment with 2-deoxyglucose, an inhibitor of glycolysis, led to cell death in mouse, but not in human macrophages. Finally, glycolysis appeared to be critical for LPS-mediated induction of the anti-inflammatory cytokine interleukin-10 in both human and mouse macrophages. In summary, these findings indicate that LPS-induced immunometabolism in human macrophages is different to that observed in mouse macrophages.
TL;DR: A physiological and oncogenic role of WTp53 is discovered in suppressing pyruvate-driven oxidative phosphorylation by inducing PUMA, which is instrumental for cancer drug discovery aiming at activatingWTp53 or restoring WTp 53 activity to p53 mutants.
TL;DR: It is revealed that the NOS cofactor tetrahydrobiopterin (BH4) modulates IL-1β production and key aspects of metabolic remodeling in activated murine macrophages via NO production and NO modulates levels of the essential TCA cycle metabolites citrate and succinate, as well as the inflammatory mediator itaconate.
TL;DR: The aim of the present review was to describe the recent discoveries associated with the deregulatory mechanisms of the PPP and glycolysis in malignant tumors, particularly in hepatocellular carcinoma, breast and lung cancer.
Abstract: Interest in cancer metabolism has increased in recent years. The pentose phosphate pathway (PPP) is a major glucose catabolism pathway that directs glucose flux to its oxidative branch and leads to the production of a reduced form of nicotinamide adenine dinucleotide phosphate and nucleic acid. The PPP serves a vital role in regulating cancer cell growth and involves many enzymes. The aim of the present review was to describe the recent discoveries associated with the deregulatory mechanisms of the PPP and glycolysis in malignant tumors, particularly in hepatocellular carcinoma, breast and lung cancer.
TL;DR: It is suggested that lncRNA MALAT1 contributes to HCC development by regulating cancer glucose metabolism, enhancing glycolysis, and inhibiting gluconeogenesis via elevated translation of the transcription factor TCF7L2.
Abstract: Reprogrammed glucose metabolism of enhanced aerobic glycolysis (or the Warburg effect) is known as a hallmark of cancer. The roles of long noncoding RNAs (lncRNA) in regulating cancer metabolism at the level of both glycolysis and gluconeogenesis are mostly unknown. We previously showed that lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) acts as a proto-oncogene in hepatocellular carcinoma (HCC). Here, we investigated the role of MALAT1 in regulating cancer glucose metabolism. MALAT1 upregulated the expression of glycolytic genes and downregulated gluconeogenic enzymes by enhancing the translation of the metabolic transcription factor TCF7L2. MALAT1-enhanced TCF7L2 translation was mediated by upregulation of SRSF1 and activation of the mTORC1-4EBP1 axis. Pharmacological or genetic inhibition of mTOR and Raptor or expression of a hypophosphorylated mutant version of eIF4E-binding protein (4EBP1) resulted in decreased expression of TCF7L2. MALAT1 expression regulated TCF7L2 mRNA association with heavy polysomes, probably through the TCF7L2 5'-untranslated region (UTR), as determined by polysome fractionation and 5'UTR-reporter assays. Knockdown of TCF7L2 in MALAT1-overexpressing cells and HCC cell lines affected their metabolism and abolished their tumorigenic potential, suggesting that the effects of MALAT1 on glucose metabolism are essential for its oncogenic activity. Taken together, our findings suggest that MALAT1 contributes to HCC development and tumor progression by reprogramming tumor glucose metabolism. SIGNIFICANCE: These findings show that lncRNA MALAT1 contributes to HCC development by regulating cancer glucose metabolism, enhancing glycolysis, and inhibiting gluconeogenesis via elevated translation of the transcription factor TCF7L2.
TL;DR: A fundamental difference in the metabolic requirements of human Treg and Th17 cells is exposed and a possible mechanism for manipulating the Th17:Treg cell axis is exposed.
Abstract: In this study we examined the metabolic requirements of human T helper cells and the effect of manipulating metabolic pathways in Th17 and Treg cells. The Th17:Treg cell axis is dysregulated in a number of autoimmune or inflammatory diseases and therefore it is of key importance to identify novel strategies to modulate this axis in favor of Treg cells. We investigated the role of carbohydrate and fatty acid metabolism in the regulation of human memory T helper cell subsets, in order to understand how T cells are regulated at the site of inflammation where essential nutrients including oxygen may be limiting. We found that Th17 lineage cells primarily utilize glycolysis, as glucose-deprivation and treatment with rapamycin resulted in a reduction in these cells. On the other hand, Treg cells exhibited increased glycolysis, mitochondrial respiration, and fatty acid oxidation, whereas Th17 cells demonstrated a reliance upon fatty acid synthesis. Treg cells were somewhat reliant on glycolysis, but to a lesser extent than Th17 cells. Here we expose a fundamental difference in the metabolic requirements of human Treg and Th17 cells and a possible mechanism for manipulating the Th17:Treg cell axis.
TL;DR: The studies show a complex but flexible role of the different metabolic pathways to produce ATP in the regulation of tip cell and non-tip cell differentiation and functioning during sprouting angiogenesis.
Abstract: During sprouting angiogenesis, an individual endothelial tip cell grows out from a pre-existing vascular network and guides following and proliferating stalk cells to form a new vessel. Metabolic pathways such as glycolysis and mitochondrial respiration as the major sources of adenosine 5′-triphosphate (ATP) for energy production are differentially activated in these types of endothelial cells (ECs) during angiogenesis. Therefore, we studied energy metabolism during angiogenesis in more detail in tip cell and non-tip cell human umbilical vein ECs. Small interfering RNA was used to inhibit transcription of glycolytic enzymes PFKFB3 or LDHA and mitochondrial enzyme PDHA1 to test whether inhibition of these specific pathways affects tip cell differentiation and sprouting angiogenesis in vitro and in vivo. We show that glycolysis is essential for tip cell differentiation, whereas both glycolysis and mitochondrial respiration occur during proliferation of non-tip cells and in sprouting angiogenesis in vitro and in vivo. Finally, we demonstrate that inhibition of mitochondrial respiration causes adaptation of EC metabolism by increasing glycolysis and vice versa. In conclusion, our studies show a complex but flexible role of the different metabolic pathways to produce ATP in the regulation of tip cell and non-tip cell differentiation and functioning during sprouting angiogenesis.
TL;DR: PFKFB3 has the highest kinase activity to shunt glucose toward glycolysis, whereas PFKFB4 has more FBPase-2 activity, redirecting glucose toward the pentose phosphate pathway, providing reducing power for lipid biosynthesis and scavenging reactive oxygen species.
Abstract: Background Cancer cells favor the use of less efficient glycolysis rather than mitochondrial oxidative phosphorylation to metabolize glucose, even in oxygen-rich conditions, a distinct metabolic alteration named the Warburg effect or aerobic glycolysis. In adult cells, bifunctional 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase (PFKFB) family members are responsible for controlling the steady-state cytoplasmic levels of fructose-2,6-bisphosphate, which allosterically activates 6-phosphofructo-1-kinase, the key enzyme catalyzing the rate-limiting reaction of glycolysis. PFKFB3 and PFKFB4 are the two main isoenzymes overexpressed in various human cancers. Scope of review In this review, we summarize recent findings on the glycolytic and extraglycolytic roles of PFKFB3 and PFKFB4 in cancer progression and discuss potential therapies for targeting of PFKFB3 and PFKFB4. Major conclusions PFKFB3 has the highest kinase activity to shunt glucose toward glycolysis, whereas PFKFB4 has more FBPase-2 activity, redirecting glucose toward the pentose phosphate pathway, providing reducing power for lipid biosynthesis and scavenging reactive oxygen species. Co-expression of PFKFB3 and PFKFB4 provides sufficient glucose metabolism to satisfy the bioenergetics demand and redox homeostasis requirements of cancer cells. Various reversible post-translational modifications of PFKFB3 enable cancer cells to flexibly adapt glucose metabolism in response to diverse stress conditions. In addition to playing important roles in tumor cell glucose metabolism, PFKFB3 and PFKFB4 are widely involved in multiple biological processes, such as cell cycle regulation, autophagy, and transcriptional regulation in a non-glycolysis-dependent manner.
TL;DR: The energy metabolic pathways of tumor cells, mechanism of action and cellular targets of 3-BrPA, antitumor effects, and the underlying mechanism of 2- BrPA alone or in combination with other antitumors in vitro and in vivo are described.
Abstract: Tumor formation and growth depend on various biological metabolism processes that are distinctly different with normal tissues. Abnormal energy metabolism is one of the typical characteristics of tumors. It has been proven that most tumor cells highly rely on aerobic glycolysis to obtain energy rather than mitochondrial oxidative phosphorylation (OXPHOS) even in the presence of oxygen, a phenomenon called “Warburg effect”. Thus, inhibition of aerobic glycolysis becomes an attractive strategy to specifically kill tumor cells, while normal cells remain unaffected. In recent years, a small molecule alkylating agent, 3-bromopyruvate (3-BrPA), being an effective glycolytic inhibitor, has shown great potential as a promising antitumor drug. Not only it targets glycolysis process, but also inhibits mitochondrial OXPHOS in tumor cells. Excellent antitumor effects of 3-BrPA were observed in cultured cells and tumor-bearing animal models. In this review, we described the energy metabolic pathways of tumor cells, mechanism of action and cellular targets of 3-BrPA, antitumor effects, and the underlying mechanism of 3-BrPA alone or in combination with other antitumor drugs (e.g., cisplatin, doxorubicin, daunorubicin, 5-fluorouracil, etc.) in vitro and in vivo. In addition, few human case studies of 3-BrPA were also involved. Finally, the novel chemotherapeutic strategies of 3-BrPA, including wafer, liposomal nanoparticle, aerosol, and conjugate formulations, were also discussed for future clinical application.
TL;DR: It is shown that the closely related fasting/starvation-induced forkhead transcription factors FOXK1 and FOXK2 induce aerobic glycolysis by upregulating the enzymatic machinery required for this, while at the same time suppressing further oxidation of pyruvate in the mitochondria by increasing the activity of pyRuvate dehydrogenase kinases 1 and 4.
Abstract: Adaptation to the environment and extraction of energy are essential for survival. Some species have found niches and specialized in using a particular source of energy, whereas others-including humans and several other mammals-have developed a high degree of flexibility1. A lot is known about the general metabolic fates of different substrates but we still lack a detailed mechanistic understanding of how cells adapt in their use of basic nutrients2. Here we show that the closely related fasting/starvation-induced forkhead transcription factors FOXK1 and FOXK2 induce aerobic glycolysis by upregulating the enzymatic machinery required for this (for example, hexokinase-2, phosphofructokinase, pyruvate kinase, and lactate dehydrogenase), while at the same time suppressing further oxidation of pyruvate in the mitochondria by increasing the activity of pyruvate dehydrogenase kinases 1 and 4. Together with suppression of the catalytic subunit of pyruvate dehydrogenase phosphatase 1 this leads to increased phosphorylation of the E1α regulatory subunit of the pyruvate dehydrogenase complex, which in turn inhibits further oxidation of pyruvate in the mitochondria-instead, pyruvate is reduced to lactate. Suppression of FOXK1 and FOXK2 induce the opposite phenotype. Both in vitro and in vivo experiments, including studies of primary human cells, show how FOXK1 and/or FOXK2 are likely to act as important regulators that reprogram cellular metabolism to induce aerobic glycolysis.
TL;DR: A novel link between gluconic metabolism reprogramming and uncontrolled inflammatory response in ALI is provided, suggesting glycolytic inhibition as an effective anti‐inflammatory strategy in treating ALI.
Abstract: Gluconic metabolic reprogramming, immune response, and inflammation are intimately linked. Glycolysis involves in the pathologic progress in acute and chronic inflammatory diseases. However, the involvement of glycolysis in the acute lung injury (ALI) is still unclear. This study investigated the role of glycolysis in an animal model of ALI. First, we found that lactate content in serum was remarkably increased in ALI patients and a murine model induced by intratracheal administration of lipopolysaccharide (LPS). The key proteins involving in glycolysis were robustly elevated, including HK2, PKM2, and HIF-1α. Intriguingly, inhibition of glycolysis by 2-deoxyglucose (2-DG) pronouncedly attenuated the lung tissue pathological injury, accumulation of neutrophil, oxidative stress, expression of proinflammatory factors in the lung of ALI mice induced by LPS. The 2-DG treatment also strongly suppressed the activation of the NOD-like receptor (NLR) family and pyrin domain-containing protein 3 (NLRP3) inflammasome. Furthermore, we investigated the role of glycolysis in the inflammatory response of primary murine macrophages activated by LPS in vitro. We found that the 2-DG treatment remarkably reduced the expression of proinflammatory factors induced by LPS, including tumor necrosis factor-α messenger RNA (mRNA), pro-interleukin (IL)-1β mRNA, pro-IL-18 mRNA, NLRP3 mRNA, caspase-1 mRNA, and IL-1β protein. Altogether, these data provide a novel link between gluconic metabolism reprogramming and uncontrolled inflammatory response in ALI. This study suggests glycolytic inhibition as an effective anti-inflammatory strategy in treating ALI.
TL;DR: KRAS4A interacts directly with hexokinase 1 in a GTP-dependent manner at the outer mitochondrial membrane, leading to kinase activation and an increase in glucose uptake and glycolysis in tumour cells.
Abstract: The most frequently mutated oncogene in cancer is KRAS, which uses alternative fourth exons to generate two gene products (KRAS4A and KRAS4B) that differ only in their C-terminal membrane-targeting region1. Because oncogenic mutations occur in exons 2 or 3, two constitutively active KRAS proteins-each capable of transforming cells-are encoded when KRAS is activated by mutation2. No functional distinctions among the splice variants have so far been established. Oncogenic KRAS alters the metabolism of tumour cells3 in several ways, including increased glucose uptake and glycolysis even in the presence of abundant oxygen4 (the Warburg effect). Whereas these metabolic effects of oncogenic KRAS have been explained by transcriptional upregulation of glucose transporters and glycolytic enzymes3-5, it is not known whether there is direct regulation of metabolic enzymes. Here we report a direct, GTP-dependent interaction between KRAS4A and hexokinase 1 (HK1) that alters the activity of the kinase, and thereby establish that HK1 is an effector of KRAS4A. This interaction is unique to KRAS4A because the palmitoylation-depalmitoylation cycle of this RAS isoform enables colocalization with HK1 on the outer mitochondrial membrane. The expression of KRAS4A in cancer may drive unique metabolic vulnerabilities that can be exploited therapeutically.