High Rate Of Aerobic Glycolysis Research Articles

Aerobic glycolysis, motility, and cytoskeletal remodeling

Cancer cell motility and cytoskeletal remodeling are ubiquitous processes essential in cancer progression to metastasis. The role of metabolism in driving motility processes and cytoskeletal rearrangements is not fully understood, but abnormal usage of cellular energetics is a well-documented hallmark of cancer.1 Shiraishi and colleagues now provide evidence that energy utilized for cancer cell motility and cytoskeletal rearrangement processes is derived primarily from aerobic glycolysis and not mitochondrial oxidative phosphorylation, indicative of a deep metabolic compartmentalization program within cancer cells2 (Fig. 1). Figure 1. Energy for cancer cell movement is derived from glycolysis. The authors demonstrate that more aggressive mesenchymal prostate cancer cells (PC3-EMT) exhibit an increased level of basal aerobic glycolysis relative to less aggressive epithelial prostate cancer cells (PC3-Epi) and non-cancerous human prostate epithelial cells (PrECs). These findings are consistent with the Warburg effect, which describes a high rate of aerobic glycolysis as a major consequence of tumorigenesis.3 Mitochondrial respiration is unchanged between the aggressive and less aggressive prostate cancer cells but provides the bulk of cellular energy in both groups. This finding highlights a widely held misconception about the Warburg Effect; despite the increased rate of aerobic glycolysis in tumor cells, mitochondrial respiration still provides the majority of cellular ATP. In addition, a higher glycolytic capacity in PC3-EMT cells (maximal rate of glycolysis) relative to PC3-Epi and PrECs was observed. Complementary studies were executed with the breast cancer cell line MDA-MB-231 (mesenchymal) and MDA-MB-231-EPI (overexpressing the transcription factors OVOL1 and OVOL2 which drive a mesenchymal to epithelial transition). The stable expression of OVOL1 and OVOL2 led to a decrease in proton production rate (PPR), a surrogate measurement for aerobic glycolysis, in MDA-MB-231 cells. Consistent with previous findings, these studies highlight the metabolic shift toward aerobic glycolysis in cells that display an aggressive phenotype.4 Given the importance of actin polymerization and subsequent turnover during cellular motility and cellular invasion in cancer progression,5 cytoskeletal (CSK) rearrangement was measured by measuring contractile moment, cellular movement, and focal adhesion formation. PC3-EMT cells display a greater net contractile moment and a greater capacity to remodel their cytoskeleton than PC3-Epi cells. By tracking cellular displacement over time, PC3-EMT cells displayed greater motility relative to PC3-Epi cells. Cancer cell motility in both cancer cell lines is attenuated upon addition of 2-deoxy-D-Glucose (2-DG), a potent inhibitor of aerobic glycolysis, but not upon addition of oligomycin A, an inhibitor of mitochondrial respiration (Fig. 1). Focal adhesion formation and cellular contractile moment are also dramatically decreased upon addition of 2-DG but not oligomycin A. These findings are surprising given that actin is an ATPase and that mitochondrial respiration provides the majority of cellular ATP for these cells.2,6 Taken together, these findings indicate that aerobic glycolysis but not mitochondrial respiration is necessary for cellular movement (Fig. 1). Additionally, these studies underscore the importance of aerobic glycolysis in CSK rearrangement and focal adhesion formation. This study demonstrates a direct link between aerobic glycolysis and cellular movement consistent with previous studies that describe glycolytic enzyme co-localization at sites of active actin turnover.7 Surprisingly, the source of fuel for motility appears to be more important than the amount of energy provided by a given fuel type (Fig. 1) indicative of cellular compartmentalization of metabolic flux. These findings suggest that targeting aerobic glycolysis therapeutically could curb cancer cell motility and subsequent metastasis.

Mitochondria and cancer.

Editorial Proliferating cells such as tumor cells have increased metabolic demands that include ATP, NADPH, lipids, proteins, and nucleotides to allow for a tumor cell to divide into two daughter cells [1]. Tumor cells reprogram their cell metabolism to sustain the increased metabolic demands of cell proliferation. Historically, much attention has focused on glycolysis as the central metabolic pathway important for tumor cell metabolism, an idea that stems from the observation made in 1920s by Otto Warburg that tumor slices consume glucose at a higher rate than normal tissue slices at normal oxygen levels [2]. This high rate of aerobic glycolysis is known as the Warburg effect and can be observed in proliferating tumor cells of cancer patients by the high uptake of the glucose analogue tracer 18-fluorodeoxyglucose (FDG) detected by Positron Emission Tomography (PET) technology [3]. The basis and the advantage of the Warburg effect for proliferating cells such as cancer cells had not been fully resolved until recently. Today, there is consensus that combination of gain of function of oncogenes, loss or tumor suppressor and aberrant activation of signaling pathways downstream of growth factor signaling induce the Warburg effect [4]. This increase in glucose metabolism through glycolysis allows the generation of glycolytic intermediates that funnel into biosynthetic pathways that support the production of NADPH, lipids, proteins and nucleotides [5]. However, the biochemists working on cancer metabolism decades ago realized that glucose metabolism alone could not fully support the de novo production of NADPH, ATP, lipids, nucleotides and proteins required for cell proliferation. Today, it is appreciated that mitochondrial metabolism is also essential for building blocks needed for cell proliferation. For example, phospholipid generation needed for de novo cell membranes in proliferating cells requires fatty acids and glycerol. The glycolytic intermediate dihydroxyacetone

Synaptosomal Lactate Dehydrogenase Isoenzyme Composition Is Shifted toward Aerobic Forms in Primate Brain Evolution

With the evolution of a relatively large brain size in haplorhine primates (i.e. tarsiers, monkeys, apes, and humans), there have been associated changes in the molecular machinery that delivers energy to the neocortex. Here we investigated variation in lactate dehydrogenase (LDH) expression and isoenzyme composition of the neocortex and striatum in primates using quantitative Western blotting and isoenzyme analysis of total homogenates and synaptosomal fractions. Analysis of isoform expression revealed that LDH in synaptosomal fractions from both forebrain regions shifted towards a predominance of the heart-type, aerobic isoform LDH-B among haplorhines as compared to strepsirrhines (i.e. lorises and lemurs), while in the total homogenate of the neocortex and striatum there was no significant difference in LDH isoenzyme composition between the primate suborders. The largest increase occurred in synapse-associated LDH-B expression in the neocortex, with an especially remarkable elevation in the ratio of LDH-B/LDH-A in humans. The phylogenetic variation in the ratio of LDH-B/LDH-A was correlated with species-typical brain mass but not the encephalization quotient. A significant LDH-B increase in the subneuronal fraction from haplorhine neocortex and striatum suggests a relatively higher rate of aerobic glycolysis that is linked to synaptosomal mitochondrial metabolism. Our results indicate that there is a differential composition of LDH isoenzymes and metabolism in synaptic terminals that evolved in primates to meet increased energy requirements in association with brain enlargement.

JMJD5 regulates PKM2 nuclear translocation and reprograms HIF-1α–mediated glucose metabolism

JMJD5, a Jumonji C domain-containing dioxygenase, is important for embryonic development and cancer growth. Here, we show that JMJD5 is up-regulated by hypoxia and is crucial for hypoxia-induced cell proliferation. JMJD5 interacts directly with pyruvate kinase muscle isozyme (PKM)2 to modulate metabolic flux in cancer cells. The JMJD5-PKM2 interaction resides at the intersubunit interface region of PKM2, which hinders PKM2 tetramerization and blocks pyruvate kinase activity. This interaction also influences translocation of PKM2 into the nucleus and promotes hypoxia-inducible factor (HIF)-1α-mediated transactivation. JMJD5 knockdown inhibits the transcription of the PKM2-HIF-1α target genes involved in glucose metabolism, resulting in a reduction of glucose uptake and lactate secretion in cancer cells. JMJD5, along with PKM2 and HIF-1α, is recruited to the hypoxia response element site in the lactate dehydrogenase A and PKM2 loci and mediates the recruitment of the latter two proteins. Our data uncover a mechanism whereby PKM2 can be regulated by factor-binding-induced homo/heterooligomeric restructuring, paving the way to cell metabolic reprogram.

Hexokinase 2 as oncotarget

Hexokinase 2 as oncotarget

ChemInform Abstract: Glucose Conjugation for the Specific Targeting and Treatment of Cancer

AbstractReview: 99 refs.

Glucose conjugation for the specific targeting and treatment of cancer

Cancers of diverse origins exhibit marked glucose avidity and high rates of aerobic glycolysis. Increased understanding of this dysfunctional metabolism known as the Warburg effect has led to an interest in targeting it for cancer therapy. One promising strategy for such targeting is glycoconjugation, the linking of a drug to glucose or another sugar. This review summarizes the most salient examples of glycoconjugates, in which known cytotoxins or targeted anticancer therapeutics have been linked to glucose (or another glucose transporter substrate sugar) for improved cancer targeting and selectivity. Building on these examples, this review also provides a series of guidelines for the design and mechanistic evaluation of future glycoconjugates.

Warburg Revisited: Regulation of Mitochondrial Metabolism by Voltage-Dependent Anion Channels in Cancer Cells

The bioenergetics of cancer cells is characterized by a high rate of aerobic glycolysis and suppression of mitochondrial metabolism (Warburg phenomenon). Mitochondrial metabolism requires inward and outward flux of hydrophilic metabolites, including ATP, ADP and respiratory substrates, through voltage-dependent anion channels (VDACs) in the mitochondrial outer membrane. Although VDACs were once considered to be constitutively open, closure of the VDAC is emerging as an adjustable limiter (governator) of mitochondrial metabolism. Studies of VDACs reconstituted into planar lipid bilayers show that tubulin at nanomolar concentrations decreases VDAC conductance. In tumor cell lines, microtubule-destabilizing agents increase cytoplasmic free tubulin and decrease mitochondrial membrane potential (ΔΨ(m)), whereas microtubule stabilization increases ΔΨ(m). Tubulin-dependent suppression of ΔΨ(m) is further potentiated by protein kinase A activation and glycogen synthase kinase-3β inhibition. Knockdown of different VDAC isoforms, especially of the least abundant isoform, VDAC3, also decreases ΔΨ(m), cellular ATP, and NADH/NAD+, suggesting that VDAC1 and VDAC2 are most inhibited by free tubulin. The brake on mitochondrial metabolism imposed by the VDAC governator probably is released when spindles form and free tubulin decreases as cells enter mitosis, which better provides for the high ATP demands of chromosome separation and cytokinesis. In conclusion, tubulin-dependent closure of VDACs represents a new mechanism contributing to the suppression of mitochondrial metabolism in the Warburg phenomenon.

Control of Glycolytic Flux by AMP-Activated Protein Kinase in Tumor Cells Adapted to Low pH

Tumor cells grow in nutrient- and oxygen-deprived microenvironments and adapt to the suboptimal growth conditions by altering their metabolic pathways. This adaptation process commonly results in a tumor phenotype that displays a high rate of aerobic glycolysis and aggressive tumor characteristics. The glucose regulatory molecule, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), is a bifunctional enzyme that is central to glycolytic flux and is downstream of the metabolic stress sensor AMP-activated protein kinase (AMPK), which has been suggested to modulate glycolysis and possibly activate isoforms of PFKFB, specifically PFKFB3 expressed in tumor cells. Our results demonstrated that long-term low pH exposure induced AMPK activation, which resulted in the up-regulation of PFKFB3 and an increase in its serine residue phosphorylation. Pharmacologic activation of AMPK resulted in an increase in PFKFB3 as well as an increase in glucose consumption, whereas in contrast, inhibition of AMPK resulted in the down-regulation of PFKFB3 and decreased glycolysis. PFKFB3 overexpression in DB-1 tumor cells induced a high rate of glycolysis and inhibited oxygen consumption, confirming its role in controlling glycolytic flux. These results show that low pH is a physiological stress that can promote a glycolytic phenotype commonly associated with tumorigenesis. The implications are that the tumor microenviroment contributes to tumor growth and treatment resistance.

Mitochondrial Dynamics, Biogenesis, and Function Are Coordinated with the Cell Cycle by APC/CCDH1

Cell proliferation is associated with a high rate of aerobic glycolysis, which has been widely interpreted as a compensatory mechanism for suppressed mitochondrial function, despite reports of high respiration rates. The molecular mechanisms that link cell proliferation with mitochondrial metabolism, dynamics, and biogenesis remain obscure. Here, we show thatproliferation is associated with an increase in both glycolysis and respiration, in conjunction with mitochondrial fusion and biogenesis. Changes in mitochondrial morphology and mass are due to accumulation of OPA1, MFN1, and TFAM, silencing any of which hinders cell proliferation. Moreover, the levels of OPA1, MFN1, and TFAM are regulated by the ubiquitin ligase APC/C(CDH1), which also controls proteasomal degradation of key glycolytic, glutaminolytic, and cell-cycle proteins. Thus, we have identified an important component of the molecular mechanism that coordinates cell proliferation with activation of the mitochondrial metabolic machinery that provides the necessary energy and biosynthetic substrates.

STAT3 can serve as a hit in the process of malignant transformation of primary cells

The transcription factor signal transducer and activator of transcription 3 (STAT3) acts downstream of many pro-oncogenic signals, including cytokines, growth factors and oncogenes, and is accordingly constitutively active in a wide variety of tumors that often become addicted to it. Moreover, STAT3 is a key player in mediating inflammation-driven tumorigenesis, where its aberrant continuous activation is typically triggered by local or systemic production of the pro-inflammatory cytokine IL-6. We recently showed that mouse embryonic fibroblasts (MEFs) derived from STAT3C k/in mice, which express physiological levels of the constitutively active mutant STAT3C, display features of transformed cells such as increased proliferation, resistance to apoptosis and senescence, and aerobic glycolysis. Here, we show that pre-existing constitutively active STAT3 is sufficient to prime primary MEFs for malignant transformation upon spontaneous immortalization. Transformation is strictly STAT3-dependent and correlates with high resistance to apoptosis and enhanced expression of anti-apoptotic/pro-survival genes. Additionally, hypoxia inducible factor (HIF)-1α level is elevated by twofold and contributes to STAT3 oncogenic activity by supporting high rates of aerobic glycolysis. Thus, constitutively active STAT3, an accepted essential factor for tumor growth/progression, can also act as a first hit in multistep carcinogenesis; this ability to predispose cells to malignant transformation may be particularly relevant in the pro-oncogenic niche represented by chronically inflamed tissues.

Investigating the Mechanism of Activation and Inhibition of the Phosphate Dependent Mitochondrial Glutaminase

Glutamine metabolism often plays a crucial role in the metabolism of cancer cells that exhibit high rates of aerobic glycolysis. The enzyme primarily responsible for the conversion of glutamine to glutamate, and ultimately the rate of α-ketoglutarate flux into the citric acid cycle, is the mitochondrial enzyme glutaminase. The fully processed form of the human enzyme can be expressed in bacteria, is fully active, and in this study we use a combination of techniques including MALS (Multi-Angle Light Schattering), X-ray crystallographyic, and SAXS (Small Angle X-ray Scattering) to better understand the nature of the active conformation of GAC and ultimately, how the recently described glutaminase inhibitor 968 (J.B., Wang; Cancer Cell, 2010) interacts with GAC and renders it inactive. Our results support a model whereby GAC binds phosphate that results in a change in glutaminase oligomerization, which results in active tetramers as well as higher oligomeric species. Effects of the drug 968 on the activation/oligomerization state of glutaminase will also be discussed.

Hyperpolarized 13C spectroscopy and an NMR‐compatible bioreactor system for the investigation of real‐time cellular metabolism

The purpose of this study was to combine a three-dimensional NMR-compatible bioreactor with hyperpolarized (13)C NMR spectroscopy in order to probe cellular metabolism in real time. JM1 (immortalized rat hepatoma) cells were cultured in a three-dimensional NMR-compatible fluidized bioreactor. (31)P spectra were acquired before and after each injection of hyperpolarized [1-(13)C] pyruvate and subsequent (13)C spectroscopy at 11.7 T. (1)H and two-dimensional (1)H-(1)H-total correlation spectroscopy spectra were acquired from extracts of cells grown in uniformly labeled (13)C-glucose, on a 16.4 T, to determine (13)C fractional enrichment and distribution of (13)C label. JM1 cells were found to have a high rate of aerobic glycolysis in both two-dimensional culture and in the bioreactor, with 85% of the (13)C label from uniformly labeled (13)C-glucose being present as either lactate or alanine after 23 h. Flux measurements of pyruvate through lactate dehydrogenase and alanine aminotransferase in the bioreactor system were 12.18 +/- 0.49 nmols/sec/10(8) cells and 2.39 +/- 0.30 nmols/sec/10(8) cells, respectively, were reproducible in the same bioreactor, and were not significantly different over the course of 2 days. Although this preliminary study involved immortalized cells, this combination of technologies can be extended to the real-time metabolic exploration of primary benign and cancerous cells and tissues prior to and after therapy.

Warburg effect revisited: an epigenetic link between glycolysis and gastric carcinogenesis

In cancer cells, glucose is often converted into lactic acid, which is known as the 'Warburg effect'. The reason that cancer cells have a higher rate of aerobic glycolysis, but not oxidative phosphorylation, remains largely unclear. Herein, we proposed an epigenetic mechanism of the Warburg effect. Fructose-1,6-bisphosphatase-1 (FBP1), which functions to antagonize glycolysis was downregulated through NF-kappaB pathway in Ras-transformed NIH3T3 cells. Restoration of FBP1 expression suppressed anchorage-independent growth, indicating the relevance of FBP1 downregulation in carcinogenesis. Indeed, FBP1 was downregulated in gastric carcinomas (P<0.01, n=22) and gastric cancer cell lines (57%, 4/7). Restoration of FBP1 expression reduced growth and glycolysis in gastric cancer cells. Moreover, FBP1 downregulation was reversed by pharmacological demethylation. Its promoter was hypermethylated in gastric cancer cell lines (57%, 4/7) and gastric carcinomas (33%, 33/101). Inhibition of NF-kappaB restored FBP1 expression, partially through demethylation of FBP1 promoter. Notably, Cox regression analysis revealed FBP1 promoter methylation as an independent prognosis predicator for gastric cancer (hazard ratio: 3.60, P=0.010). In summary, we found that NF-kappaB functions downstream of Ras to promote epigenetic downregulation of FBP1. Promoter methylation of FBP1 can be used as a new biomarker for prognosis prediction of gastric cancer. Such an important epigenetic link between glycolysis and carcinogenesis partly explains the Warburg effect.

Transketolase‐like protein 1 (TKTL1) is required for rapid cell growth and full viability of human tumor cells

Cancer cells display high rates of aerobic glycolysis, a phenomenon known as the Warburg effect. Lactate and pyruvate, the end products of glycolysis, are overproduced by cancer cells even in the presence of oxygen. The pentose phosphate pathway (PPP) allows glucose conversion to ribose for nucleic acid synthesis, glucose degradation to lactate, and regeneration of redox equivalents. The nonoxidative part of the PPP is controlled by transketolase (TKT) enzymes. One TKT isoform, the transketolase-like protein 1 (TKTL1) is specifically upregulated in different human cancers and its overexpression predicts a poor patient's survival. This finding implicates that an increased TKTL1 expression may activate the PPP leading to enhanced cancer cell growth and survival. To analyze the functional role of TKTL1 in malignant progression, we inhibited TKTL1 by RNAi technologies in human HCT116 colon carcinoma cells. TKTL1 suppression resulted in a significantly slowed cell growth, glucose consumption and lactate production. In TKTL1 knockdown-cells, the intracellular reactive oxygen species levels were not significantly increased, whereas the sensitivity towards oxidative stress-induced apoptosis was clearly enhanced. These data provide new clues on the importance of TKTL1 dys-regulation in tumor cells and indicate that TKTL1 overexpression may be considered not only as a new tumor marker but also as a good target for anticancer therapy.

Inhibition of phosphatidylinositol 3-kinase-mediated glucose metabolism coincides with resveratrol-induced cell cycle arrest in human diffuse large B-cell lymphomas

An abnormally high rate of aerobic glycolysis is characteristic of many transformed cells. Here we report the polyphenolic compound, resveratrol, inhibited phosphatidylinositol 3-kinase (PI-3K) signaling and glucose metabolism, coinciding with cell-cycle arrest, in germinal center (GC)-like LY1 and LY18 human diffuse large B-cell lymphomas (DLBCLs). Specifically, resveratrol inhibited the phosphorylation of Akt, p70 S6K, and S6 ribosomal protein on activation residues. Biochemical analyses and nuclear magnetic resonance spectroscopy identified glycolysis as the primary glucose catabolic pathway in LY18 cells. Treatment with the glycolytic inhibitor 2-deoxy- d-glucose, resulted in accumulation of LY18 cells in G 0/G 1-phase, underscoring the biological significance of glycolysis in growth. Glycolytic flux was inhibited by the PI-3K inhibitor LY294002, suggesting a requirement for PI-3K activity in glucose catabolism. Importantly, resveratrol treatment resulted in inhibition of glycolysis. Decreased glycolytic flux corresponded to a parallel reduction in the expression of several mRNAs encoding rate-limiting glycolytic enzymes. These results are the first to identify as a mechanism underlying resveratrol-induced growth arrest, the inhibition of glucose catabolism by the glycolytic pathway. Taken together, these results raise the possibility that inhibition of signaling and metabolic pathways that control glycolysis might be effective in therapy of DLBCLs.

Cancer cell death by programmed necrosis?

A recent paper by Zong et al. describes how alkylating agents kill cells by a process they term "programmed necrosis," induced by excessive activation of PARP resulting in degradation of cytosolic NAD(+) and inhibition of glycolysis. We argue that it is not obvious whether chemotherapy in patients can induce sufficient NAD(+) loss to affect glycolysis; that the "programmed" nature of the necrosis requires more evidence; and that there are mechanisms making cancer cells hypersensitive to DNA damage other than their high rate of aerobic glycolysis.

Akt stimulates aerobic glycolysis in cancer cells.

Cancer cells frequently display high rates of aerobic glycolysis in comparison to their nontransformed counterparts, although the molecular basis of this phenomenon remains poorly understood. Constitutive activity of the serine/threonine kinase Akt is a common perturbation observed in malignant cells. Surprisingly, although Akt activity is sufficient to promote leukemogenesis in nontransformed hematopoietic precursors and maintenance of Akt activity was required for rapid disease progression, the expression of activated Akt did not increase the proliferation of the premalignant or malignant cells in culture. However, Akt stimulated glucose consumption in transformed cells without affecting the rate of oxidative phosphorylation. High rates of aerobic glycolysis were also identified in human glioblastoma cells possessing but not those lacking constitutive Akt activity. Akt-expressing cells were more susceptible than control cells to death after glucose withdrawal. These data suggest that activation of the Akt oncogene is sufficient to stimulate the switch to aerobic glycolysis characteristic of cancer cells and that Akt activity renders cancer cells dependent on aerobic glycolysis for continued growth and survival.

Hexokinase II: the integration of energy metabolism and control of apoptosis.

Hexokinase II is often highly expressed in poorly differentiated and rapidly growing tumors that exhibit a high rate of aerobic glycolysis. Hexokinase II binds to the mitochondrial membrane through its interaction with the outer membrane voltage-dependent anion channel (VDAC), preferentially at contact sites between the outer and inner mitochondrial membrane. This location is thought to be important for the integration of glycolysis with mitochondrial energy metabolism. VDAC is a critical component of the mitochondrial phase of apoptosis and its interaction with Bcl-2 family proteins controls the rate of release of mitochondrial intermembrane space proteins that activate the execution phase of apoptosis. The proteins involved in the contact sites also constitute the mitochondrial permeability transition, one of the mechanisms by which mitochondrial protein release can be mediated. Hexokinase II binding to VDAC suppresses the release of intermembrane space proteins and inhibits apoptosis, thereby contributing to the survival advantage of tumor cells. This interaction places hexokinase II in a position to integrate glycolytic metabolism of the tumor cell with the control of apoptosis at the mitochondrial level. Mitochondrial binding of hexokinase II may constitute an attractive target for therapeutic intervention to suppress tumor growth.

Hypoxia-inducible Factor 1 Activation by Aerobic Glycolysis Implicates the Warburg Effect in Carcinogenesis

Cancer cells display high rates of aerobic glycolysis, a phenomenon known historically as the Warburg effect. Lactate and pyruvate, the end products of glycolysis, are highly produced by cancer cells even in the presence of oxygen. Hypoxia-induced gene expression in cancer cells has been linked to malignant transformation. Here we provide evidence that lactate and pyruvate regulate hypoxia-inducible gene expression independently of hypoxia by stimulating the accumulation of hypoxia-inducible Factor 1alpha (HIF-1alpha). In human gliomas and other cancer cell lines, the accumulation of HIF-1alpha protein under aerobic conditions requires the metabolism of glucose to pyruvate that prevents the aerobic degradation of HIF-1alpha protein, activates HIF-1 DNA binding activity, and enhances the expression of several HIF-1-activated genes including erythropoietin, vascular endothelial growth factor, glucose transporter 3, and aldolase A. Our findings support a novel role for pyruvate in metabolic signaling and suggest a mechanism by which high rates of aerobic glycolysis can promote the malignant transformation and survival of cancer cells.