Aerobic Glycolysis: Meeting the Metabolic Requirements of Cell Proliferation

Lunt, Sophia Y.; Heiden, Matthew G. Vander

doi:10.1146/annurev-cellbio-092910-154237

Cited by 2,536 publications

(2,445 citation statements)

References 155 publications

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“…We examined the expression of monocarboxylate transporters (MCT), which transport lactate across membranes 26 and found that among 7 MCTs, the MCT1 transcript was significantly induced by 0.1 Gy treatment ( Figure 2b). As lactate can be produced as the end product of glycolysis, 19,20 we measured glucose levels and detected an increase in glucose consumption induced by 0.1 Gy but not 4 Gy irradiation ( Figure 2c). Together with an elevated extracellular acidification rate (ECAR) in 0.1 Gy-treated cells, measured with a Seahorse XF Analyzer (Figure 2d), the results suggest an induction of glycolysis specific to low-dose IR.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, 0.1 Gy treatment of human fibroblasts also induced an increase in GLUT-1 and GLUT-3 at both the mRNA (Figure 2j) and the protein levels (Figure 2k), consistent with increased glucose flux. 20 The glycolytic switch is necessary for low-dose IRinduced resistance. The low-dose IR-induced glycolytic shift under normoxic conditions is similar to the 'Warburg effect', which has been shown to have an important role in promoting cancer cell proliferation and survival.…”

Section: Resultsmentioning

confidence: 99%

“…10 Upon induction, HIF-1a stimulates transcription of genes encoding glucose transporters and enzymes of glycolysis and the pentose phosphate pathway (PPP). 19,20 HIF-1a also negatively regulates TCA cycle enzymes, indirectly through inducing miR120. 21,22 In this report, we describe a previously unrecognized metabolic response to low-dose radiation.…”

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confidence: 99%

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Low-dose radiation exposure induces a HIF-1-mediated adaptive and protective metabolic response

et al. 2014

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Because of insufficient understanding of the molecular effects of low levels of radiation exposure, there is a great uncertainty regarding its health risks. We report here that treatment of normal human cells with low-dose radiation induces a metabolic shift from oxidative phosphorylation to aerobic glycolysis resulting in increased radiation resistance. This metabolic change is highlighted by upregulation of genes encoding glucose transporters and enzymes of glycolysis and the oxidative pentose phosphate pathway, concomitant with downregulation of mitochondrial genes, with corresponding changes in metabolic flux through these pathways. Mechanistically, the metabolic reprogramming depends on HIF1a, which is induced specifically by lowdose irradiation linking the metabolic pathway with cellular radiation dose response. Increased glucose flux and radiation resistance from low-dose irradiation are also observed systemically in mice. This highly sensitive metabolic response to lowdose radiation has important implications in understanding and assessing the health risks of radiation exposure.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Low-dose radiation exposure induces a HIF-1-mediated adaptive and protective metabolic response

et al. 2014

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“…40 Activated T cells change their metabolic state by utilizing aerobic glycolysis. [41][42][43] The high rate of glycolysis in activated T cells bypasses the normal oxidation of pyruvate in the mitochondria, resulting in lactic acid fermentation, whereas minimal lactic acid production occurs in resting cells.…”

Section: Discussionmentioning

confidence: 99%

T-cell development of resistance to apoptosis is driven by a metabolic shift in carbon source and altered activation of death pathways

et al. 2015

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We developed a model system to investigate apoptotic resistance in T cells using osmotic stress (OS) to drive selection of deathresistant cells. Exposure of S49 (Neo) T cells to multiple rounds of OS followed by recovery of surviving cells resulted in the selection of a population of T cells (S49 ) that failed to die in response to a variety of intrinsic apoptotic stimuli including acute OS, but remained sensitive to extrinsic apoptotic initiators. Genome-wide microarray analysis comparing the S49 (OS 4-25) with the parent S49 (Neo) cells revealed over 8500 differentially regulated genes, with almost 90% of those identified being repressed. Surprisingly, our data revealed that apoptotic resistance is not associated with expected changes in pro-or antiapoptotic Bcl-2 family member genes. Rather, these cells lack several characteristics associated with the initial signaling or activation of the intrinsic apoptosis pathway, including failure to increase mitochondrial-derived reactive oxygen species, failure to increase intracellular calcium, failure to deplete glutathione, failure to release cytochrome c from the mitochondria, along with a lack of induced caspase activity. The S49 (OS 4-25) cells exhibit metabolic characteristics indicative of the Warburg effect, and, despite numerous changes in mitochondria gene expression, the mitochondria have a normal metabolic capacity. Interestingly, the S49 (OS 4-25) cells have developed a complete dependence on glucose for survival, and glucose withdrawal results in cell death with many of the essential characteristics of apoptosis. Furthermore, we show that other dietary sugars such as galactose support the viability of the S49 (OS 4-25) cells in the absence of glucose; however, this carbon source sensitizes these cells to die. Our findings suggest that carbon substrate reprogramming for energy production in the S49 (OS 4-25) cells results in stimulusspecific recognition defects in the activation of intrinsic apoptotic pathways.

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“…Metabolic transformation in cancer supports macromolecule biosynthesis and is crucial for cancer cell survival and tumour formation [1,2]. Many solid tumours exhibit increased glucose uptake and lactate secretion, a feature known as the Warburg effect.…”

Section: Introductionmentioning

confidence: 99%

Functional screening identifies MCT4 as a key regulator of breast cancer cell metabolism and survival

Baenke

Dubuis

Brault³

et al. 2015

The Journal of Pathology

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Metabolic reprogramming in cancer enhances macromolecule biosynthesis and supports cell survival. Oncogenic drivers affect metabolism by altering distinct metabolic processes and render cancer cells sensitive to perturbations of the metabolic network. This study aimed to identify selective metabolic dependencies in breast cancer by investigating 17 breast cancer cells lines representative of the genetic diversity of the disease. Using a functional screen, we demonstrate here that monocarboxylate transporter 4 (MCT4) is an important regulator of breast cancer cell survival. MCT4 supports pH maintenance, lactate secretion and non-oxidative glucose metabolism in breast cancer cells. Moreover, MCT4 depletion caused an increased dependence of cancer cells on mitochondrial respiration and glutamine metabolism. MCT4 depletion reduced the ability of breast cancer cells to grow in a three-dimensional (3D) matrix or as multilayered spheroids. Moreover, MCT4 expression is regulated by the PI3K-Akt signalling pathway and highly expressed in HER2-positive breast cancers. These results suggest that MCT4 is a potential therapeutic target in defined breast cancer subtypes and reveal novel avenues for combination treatment.

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Aerobic Glycolysis: Meeting the Metabolic Requirements of Cell Proliferation

Cited by 2,536 publications

References 155 publications

Low-dose radiation exposure induces a HIF-1-mediated adaptive and protective metabolic response

Low-dose radiation exposure induces a HIF-1-mediated adaptive and protective metabolic response

T-cell development of resistance to apoptosis is driven by a metabolic shift in carbon source and altered activation of death pathways

Functional screening identifies MCT4 as a key regulator of breast cancer cell metabolism and survival

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