Modeling cancer glycolysis

Marín‐Hernández, Álvaro; Gallardo‐Pérez, Juan Carlos; Rodrı́guez-Enrı́quez, Sara; Encalada, Rusely; Moreno‐Sánchez, Rafael; Saavedra, Emma

doi:10.1016/j.bbabio.2010.11.006

Cited by 118 publications

(146 citation statements)

References 54 publications

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“…1 pmol ATP, it would need about 3 h to produce this amount of ATP from oxidative phosphorylation to support nucleotide synthesis alone. However, hypoxic cells also ferment glucose to lactate, producing 2 ATP/mol glucose and in cancer cells glycolysis is typically accelerated many fold (42,121–122), which may produce ATP at a rate comparable to the more efficient mitochondrial oxidation of fuels including fatty acids (104,123), Gln (25,44–45,81,106,119,124–127) and ketone bodies (46) (Supplementary Table S2). It is notable that in the interstitial fluid of solid tumors, the glucose levels are very low with depletion of lipids compared with the blood supply in the tumor (128).…”

Section: Nucleic Acid Synthesis: Energetics and Nutrient Requirementsmentioning

confidence: 99%

Regulation of mammalian nucleotide metabolism and biosynthesis

Lane

Fan

2015

Nucleic Acids Research

651

558

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Nucleotides are required for a wide variety of biological processes and are constantly synthesized de novo in all cells. When cells proliferate, increased nucleotide synthesis is necessary for DNA replication and for RNA production to support protein synthesis at different stages of the cell cycle, during which these events are regulated at multiple levels. Therefore the synthesis of the precursor nucleotides is also strongly regulated at multiple levels. Nucleotide synthesis is an energy intensive process that uses multiple metabolic pathways across different cell compartments and several sources of carbon and nitrogen. The processes are regulated at the transcription level by a set of master transcription factors but also at the enzyme level by allosteric regulation and feedback inhibition. Here we review the cellular demands of nucleotide biosynthesis, their metabolic pathways and mechanisms of regulation during the cell cycle. The use of stable isotope tracers for delineating the biosynthetic routes of the multiple intersecting pathways and how these are quantitatively controlled under different conditions is also highlighted. Moreover, the importance of nucleotide synthesis for cell viability is discussed and how this may lead to potential new approaches to drug development in diseases such as cancer.

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Section: Nucleic Acid Synthesis: Energetics and Nutrient Requirementsmentioning

confidence: 99%

Regulation of mammalian nucleotide metabolism and biosynthesis

Lane

Fan

2015

Nucleic Acids Research

651

558

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“…However, the various components of this dynamic system cannot be simultaneously accessed by experimental studies in single living cells. This necessitates the use of mathematical models (21)(22)(23)(24)(25)(26)(27).…”

Section: Introductionmentioning

confidence: 99%

Mitoenergetic Dysfunction Triggers a Rapid Compensatory Increase in Steady-State Glucose Flux

Liemburg-Apers

Schirris

Rüssel

et al. 2015

Biophysical Journal

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ATP can be produced in the cytosol by glycolytic conversion of glucose (GLC) into pyruvate. The latter can be metabolized into lactate, which is released by the cell, or taken up by mitochondria to fuel ATP production by the tricarboxylic acid cycle and oxidative phosphorylation (OXPHOS) system. Altering the balance between glycolytic and mitochondrial ATP generation is crucial for cell survival during mitoenergetic dysfunction, which is observed in a large variety of human disorders including cancer. To gain insight into the kinetic properties of this adaptive mechanism we determined here how acute (30 min) inhibition of OXPHOS affected cytosolic GLC homeostasis. GLC dynamics were analyzed in single living C2C12 myoblasts expressing the fluorescent biosensor FLII(12)Pglu-700μδ6 (FLII). Following in situ FLII calibration, the kinetic properties of GLC uptake (V1) and GLC consumption (V2) were determined independently and used to construct a minimal mathematical model of cytosolic GLC dynamics. After validating the model, it was applied to quantitatively predict V1 and V2 at steady-state (i.e., when V1 = V2 = Vsteady-state) in the absence and presence of OXPHOS inhibitors. Integrating model predictions with experimental data on lactate production, cell volume, and O2 consumption revealed that glycolysis and mitochondria equally contribute to cellular ATP production in control myoblasts. Inhibition of OXPHOS induced a twofold increase in Vsteady-state and glycolytic ATP production flux. Both in the absence and presence of OXPHOS inhibitors, GLC was consumed at near maximal rates, meaning that GLC consumption is rate-limiting under steady-state conditions. Taken together, we demonstrate here that OXPHOS inhibition increases steady-state GLC uptake and consumption in C2C12 myoblasts. This activation fully compensates for the reduction in mitochondrial ATP production, thereby maintaining the balance between cellular ATP supply and demand.

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“…Moreover, tumours can also metabolise glucose through the pentose phosphate pathway (PPP) to produce ribose 5-phosphate for de novo synthesis of nucleotides and nicotinamide adenine dinucleotide phosphate (NADPH) for all the anabolic process (Marin-Hernandez et al 2011). …”

Section: Alterations In Mitochondrial Bioenergetics In Cancer Cellsmentioning

confidence: 99%

Targeting Mitochondria: A Powerhouse Approach to Cancer Treatment

Agnihotri

Rani

Kumar

2014

Multi-Targeted Approach to Treatment of Cancer

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The central role that mitochondria play in cancer progression was highlighted by Otto Warburg in 1920s. He inferred that malignant cells synthesise ATP by metabolising glucose predominantly through glycolytic pathway rather than more efficient process of oxidative phosphorylation He proposed that such glycolytic ATP production is a universal property of malignant cells and that an impaired mitochondrial metabolism is a key event in development of carcinogenesis. More recent studies have revealed that in addition to their role in energy metabolism, mitochondria are also crucial regulator of apoptosis, a fundamental cellular function by which cells die in a well-controlled or programmed manner. Evasion of apoptosis is an important hallmark of cancer cell and a major cause of treatment failure. Therefore, targeting mitochondria is considered a promising strategy as it not only would affect the energy-dependent cell survival but also initiates the apoptotic pathway. This chapter would focus on the altered mitochondrial bioenergetics in tumour cells and their therapeutic implications.

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Modeling cancer glycolysis

Cited by 118 publications

References 54 publications

Regulation of mammalian nucleotide metabolism and biosynthesis

Regulation of mammalian nucleotide metabolism and biosynthesis

Mitoenergetic Dysfunction Triggers a Rapid Compensatory Increase in Steady-State Glucose Flux

Targeting Mitochondria: A Powerhouse Approach to Cancer Treatment

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