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Cited by 199Cancer, Hypoxia, and MetabolismMetabolism, Diabetes, and CancerCancer, Lipids, and Metabolism

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The Role for Myc in Coordinating Glycolysis, Oxidative Phosphorylation, Glutaminolysis, and Fatty Acid Metabolism in Normal and Neoplastic Tissues

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Goetzman, Eric S., Prochownik, Edward V.·2018·Frontiers in Endocrinology
DOI 10.3389/fendo.2018.00129PMC PMC5907532
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Abstract

That cancer cells show patterns of metabolism different from normal cells has been known for over 50 years. Yet, it is only in the past decade or so that an appreciation of the benefits of these changes has begun to emerge. Altered cancer cell metabolism was initially attributed to defective mitochondria. However, we now realize that most cancers do not have mitochondrial mutations and that normal cells can transiently adopt cancer-like metabolism during periods of rapid proliferation. Indeed, an encompassing, albeit somewhat simplified, conceptual framework to explain both normal and cancer cell metabolism rests on several simple premises. First, the metabolic pathways used by cancer cells and their normal counterparts are the same. Second, normal quiescent cells use their metabolic pathways and the energy they generate largely to maintain cellular health and organelle turnover and, in some cases, to provide secreted products necessary for the survival of the intact organism. By contrast, undifferentiated cancer cells minimize the latter functions and devote their energy to producing the anabolic substrates necessary to maintain high rates of unremitting cellular proliferation. Third, as a result of the uncontrolled proliferation of cancer cells, a larger fraction of the metabolic intermediates normally used by quiescent cells purely as a source of energy are instead channeled into competing proliferation-focused and energy-consuming anabolic pathways. Fourth, cancer cell clones with the most plastic and rapidly adaptable metabolism will eventually outcompete their less well-adapted brethren during tumor progression and evolution. This attribute becomes increasingly important as tumors grow and as their individual cells compete in a constantly changing and inimical environment marked by nutrient, oxygen, and growth factor deficits. Here, we review some of the metabolic pathways whose importance has gained center stage for tumor growth, particularly those under the control of the c-Myc (Myc) oncoprotein. We discuss how these pathways differ functionally between quiescent and proliferating normal cells, how they are kidnapped and corrupted during the course of transformation, and consider potential therapeutic strategies that take advantage of common features of neoplastic and metabolic disorders.

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Figure 1 Control and distribution of ATP and reducing equivalents derived from glycolysis and oxidative phosphorylation (OXPHOS). Under normal aerobic conditions, most glycolysis-derived pyruvate produced by quiescent or slowly growing cells is converted to acetyl-CoA (AcCoA) in the mitochondria, with little being converted into lactate. This provides the mitochondrial reducing equivalents, in the form of NADH and FADH2, to power the electron transport chain (ETC), to generate a proton gradient (ΔΨM) and to establish the protomotive force necessary to drive ATP generation via Complex V. Excess cytoplasmic reducing equivalents in the form of NADH may be transferred to the mitochondria via the glycerol-3-phosphate and malate–aspartate shuttles and can potentially support OXPHOS when AcCoA levels are low. During hypoxia, glucose uptake, glycolytically derived ATP synthesis, and the “A” isoform of LDH (LDH-A)-catalyzed conversion of pyruvate to lactate are accelerated due to an inability of the ETC to reduce molecular oxygen to water and generate TCA cycle-derived ATP. Most pyruvate will be converted to lactate, thereby generating more NAD+ and sustaining anaerobic glycolysis. This positive feedback loop ensures a constant and balanced source of ATP as an energy source and the regeneration of NAD+ to serve as an electron acceptor for continued glycolysis. By contrast, dividing cells have “divided loyalties” with regard to the disposition of glycolytic intermediates, with some being used to generate pyruvate and others being used as anabolic building blocks. Just as glycolysis and lactate production engage in a positive feedback loop to provide a balanced amount of NAD+ and NADH in support of one another’s activity, the pentose phosphate pathway (PPP) and the biosynthesis of fatty acids and sterols, generate NADPH and NADP+, respectively, to support each others’ pathways. The pyruvate dehydrogenase complex (PDC), which includes pyruvate dehydrogenase, is the key enzymatic complex that connects glycolysis to the TCA cycle. It catalyzes the conversion of the last product of glycolysis, pyruvate, to the entry-level substrate for the TCA cycle, AcCoA. In doing so, it contributes one-fourth of the NADH that is produced by a single round of the TCA cycle.
Figure 1 Control and distribution of ATP and reducing equivalents derived from glycolysis and oxidative phosphorylation (OXPHOS). Under normal aerobic conditions, most glycolysis-derived pyruvate produced by quiescent or slowly growing cells is converted to acetyl-CoA (AcCoA) in the mitochondria, with little being converted into lactate. This provides the mitochondrial reducing equivalents, in the form of NADH and FADH2, to power the electron transport chain (ETC), to generate a proton gradient (ΔΨM) and to establish the protomotive force necessary to drive ATP generation via Complex V. Excess cytoplasmic reducing equivalents in the form of NADH may be transferred to the mitochondria via the glycerol-3-phosphate and malate–aspartate shuttles and can potentially support OXPHOS when AcCoA levels are low. During hypoxia, glucose uptake, glycolytically derived ATP synthesis, and the “A” isoform of LDH (LDH-A)-catalyzed conversion of pyruvate to lactate are accelerated due to an inability of the ETC to reduce molecular oxygen to water and generate TCA cycle-derived ATP. Most pyruvate will be converted to lactate, thereby generating more NAD+ and sustaining anaerobic glycolysis. This positive feedback loop ensures a constant and balanced source of ATP as an energy source and the regeneration of NAD+ to serve as an electron acceptor for continued glycolysis. By contrast, dividing cells have “divided loyalties” with regard to the disposition of glycolytic intermediates, with some being used to generate pyruvate and others being used as anabolic building blocks. Just as glycolysis and lactate production engage in a positive feedback loop to provide a balanced amount of NAD+ and NADH in support of one another’s activity, the pentose phosphate pathway (PPP) and the biosynthesis of fatty acids and sterols, generate NADPH and NADP+, respectively, to support each others’ pathways. The pyruvate dehydrogenase complex (PDC), which includes pyruvate dehydrogenase, is the key enzymatic complex that connects glycolysis to the TCA cycle. It catalyzes the conversion of the last product of glycolysis, pyruvate, to the entry-level substrate for the TCA cycle, AcCoA. In doing so, it contributes one-fourth of the NADH that is produced by a single round of the TCA cycle.CC BY · PubMed Central
Figure 2 The balance between glycolysis and oxidative phosphorylation (OXPHOS) in normal and tumor cells. The sizes of the triangles are meant to indicate the relative metabolic activity under each of the depicted conditions. (A) Under aerobic conditions, glucose in quiescent, non-proliferating cells is converted in a linear fashion into pyruvate, which is then consumed by the TCA cycle to produce the bulk of ATP (Figure 1). (B) Under hypoxic periods in these same cells, OXPHOS is no longer able to furnish ATP. Energy production then switches rapidly to glycolysis, which can temporarily maintain energy supplies. Both glucose uptake and glycolysis can be highly upregulated although at the expense of generating considerable amounts of lactate. (C) In well-oxygenated, rapidly proliferating tumor cells and normal cells, glycolysis and OXPHOS are both upregulated and balanced so as to provide for the most efficient production of ATP, the most rapid biomass accumulation and the most rapid rate of proliferation. The metabolic building blocks for these processes are derived from both the glycolytic pathway and the TCA cycle, thus explaining the need for each. Examples of the first include the diversion of glucose-6-phosphate into the pentose phosphate pathway to provide pentose sugars for nucleotide synthesis (Figure 1), the diversion of 3-phosphoglycerate for the synthesis of purine nucleotides and the diversion of phosphoenol pyruvate for the synthesis of tyrosine, tryptophan, and phenylalanine. Examples of the second include the transport of citrate into the cytoplasm for use in fatty acid and sterol biosynthesis and the diversion of oxaloacetate into the cytoplasm for conversion in aspartate, asparagine, and pyrimidine nucleotides. While the graphic here depicts an equal contribution by both glycolysis and OXPHOS, their relative contribution to overall metabolism can shift in response to proliferative rates (indicated by the small blue boxes), oxygen tension, and the supply of environmentally derived nutrients. In rare cancers, mutations in select TCA cycle genes can impart increased, and less reversible, reliance on aerobic glycolysis as a means of generating energy, thus confirming to Warburg’s original explanation of his eponymous effect (41–43).
Figure 2 The balance between glycolysis and oxidative phosphorylation (OXPHOS) in normal and tumor cells. The sizes of the triangles are meant to indicate the relative metabolic activity under each of the depicted conditions. (A) Under aerobic conditions, glucose in quiescent, non-proliferating cells is converted in a linear fashion into pyruvate, which is then consumed by the TCA cycle to produce the bulk of ATP (Figure 1). (B) Under hypoxic periods in these same cells, OXPHOS is no longer able to furnish ATP. Energy production then switches rapidly to glycolysis, which can temporarily maintain energy supplies. Both glucose uptake and glycolysis can be highly upregulated although at the expense of generating considerable amounts of lactate. (C) In well-oxygenated, rapidly proliferating tumor cells and normal cells, glycolysis and OXPHOS are both upregulated and balanced so as to provide for the most efficient production of ATP, the most rapid biomass accumulation and the most rapid rate of proliferation. The metabolic building blocks for these processes are derived from both the glycolytic pathway and the TCA cycle, thus explaining the need for each. Examples of the first include the diversion of glucose-6-phosphate into the pentose phosphate pathway to provide pentose sugars for nucleotide synthesis (Figure 1), the diversion of 3-phosphoglycerate for the synthesis of purine nucleotides and the diversion of phosphoenol pyruvate for the synthesis of tyrosine, tryptophan, and phenylalanine. Examples of the second include the transport of citrate into the cytoplasm for use in fatty acid and sterol biosynthesis and the diversion of oxaloacetate into the cytoplasm for conversion in aspartate, asparagine, and pyrimidine nucleotides. While the graphic here depicts an equal contribution by both glycolysis and OXPHOS, their relative contribution to overall metabolism can shift in response to proliferative rates (indicated by the small blue boxes), oxygen tension, and the supply of environmentally derived nutrients. In rare cancers, mutations in select TCA cycle genes can impart increased, and less reversible, reliance on aerobic glycolysis as a means of generating energy, thus confirming to Warburg’s original explanation of his eponymous effect (41–43).CC BY · PubMed Central
Figure 3 Reprogramming of glutamine metabolism by rapidly proliferating cells. Extracellular glutamine, along with several other amino acids, is delivered to the cytosol by the SLC1A5/ASCT2 or SN2 transporters (212–214). Together, these contribute to de novo protein biosynthesis, whereas aspartate is also used in purine and pyrimidine synthetic pathways. In addition, glutamine can undergo reductive carboxylation to supply citrate, which can be converted by ATP citrate lyase to supply cytosolic acetyl-CoA (AcCoA) for de novo lipid synthesis (216, 217). Finally, glutamine can be catalyzed by glutamine synthase 1 (Gls1)/2 and then to α-ketoglutarate by the mitochondrial enzyme glutamine dehydrogenase generating a molecule of NADH (or NADPH) in a glycolysis-independent manner. α-Ketoglutarate can also be furnished via the action of glutamine pyruvate transaminase (GPT) or glutamate oxaloacetate transaminase (GOT), which utilize pyruvate or oxaloacetate, respectively, in reactions that also yield alanine and aspartic acid. Taken together, glutaminolysis thus coordinates amino acid, lipid, and nucleoside biosynthesis while concurrently providing energy to support these processes and contributing to the anaplerotic substrate supply.
Figure 3 Reprogramming of glutamine metabolism by rapidly proliferating cells. Extracellular glutamine, along with several other amino acids, is delivered to the cytosol by the SLC1A5/ASCT2 or SN2 transporters (212–214). Together, these contribute to de novo protein biosynthesis, whereas aspartate is also used in purine and pyrimidine synthetic pathways. In addition, glutamine can undergo reductive carboxylation to supply citrate, which can be converted by ATP citrate lyase to supply cytosolic acetyl-CoA (AcCoA) for de novo lipid synthesis (216, 217). Finally, glutamine can be catalyzed by glutamine synthase 1 (Gls1)/2 and then to α-ketoglutarate by the mitochondrial enzyme glutamine dehydrogenase generating a molecule of NADH (or NADPH) in a glycolysis-independent manner. α-Ketoglutarate can also be furnished via the action of glutamine pyruvate transaminase (GPT) or glutamate oxaloacetate transaminase (GOT), which utilize pyruvate or oxaloacetate, respectively, in reactions that also yield alanine and aspartic acid. Taken together, glutaminolysis thus coordinates amino acid, lipid, and nucleoside biosynthesis while concurrently providing energy to support these processes and contributing to the anaplerotic substrate supply.CC BY · PubMed Central
Figure 4 Regulation of neutral lipid accumulation in myc−/− hepatocytes is both Myc dependent and Myc independent. (A) In myc+/+ hepatocytes, the pathways indicated by red arrows are regulated both by Myc and Myc-independent factors. Stored lipid and circulating lipid are maintained in equilibrium. Stored lipid contributes minimally to energy generation (via FAO) or the synthesis of new membranes or other lipids when ATP and acetyl-CoA (AcCoA) are derived via glycolysis. Under these conditions, lipids such as fatty acids and sterols are largely synthesized from cytoplasmic AcCoA that originates from TCA cycle-derived citrate. (B) In myc−/− hepatocytes, basal rates of glycolysis, oxidative phosphorylation, and fatty acid synthesis are depressed thereby allowing for a compensatory increase in FAO. This allows basal levels of ATP and AcCoA to be sustained to meet energetic needs. New membrane synthesis thus becomes more reliant upon the uptake of exogenous lipids, which accumulate in the form of neutral lipids, leading to mitochondrial dysfunction and reactive oxygen species (ROS) generation (254–256). Additional ROS are generated as a result of the accumulation of intracellular and extracellular neutral lipid (257–259).
Figure 4 Regulation of neutral lipid accumulation in myc−/− hepatocytes is both Myc dependent and Myc independent. (A) In myc+/+ hepatocytes, the pathways indicated by red arrows are regulated both by Myc and Myc-independent factors. Stored lipid and circulating lipid are maintained in equilibrium. Stored lipid contributes minimally to energy generation (via FAO) or the synthesis of new membranes or other lipids when ATP and acetyl-CoA (AcCoA) are derived via glycolysis. Under these conditions, lipids such as fatty acids and sterols are largely synthesized from cytoplasmic AcCoA that originates from TCA cycle-derived citrate. (B) In myc−/− hepatocytes, basal rates of glycolysis, oxidative phosphorylation, and fatty acid synthesis are depressed thereby allowing for a compensatory increase in FAO. This allows basal levels of ATP and AcCoA to be sustained to meet energetic needs. New membrane synthesis thus becomes more reliant upon the uptake of exogenous lipids, which accumulate in the form of neutral lipids, leading to mitochondrial dysfunction and reactive oxygen species (ROS) generation (254–256). Additional ROS are generated as a result of the accumulation of intracellular and extracellular neutral lipid (257–259).CC BY · PubMed Central
Figure 5 Co-regulation of glycolysis and FAO. Starvation or glucose deprivation mobilizes lipolytic pathways and upregulates FAO to provide an alternate source of acetyl-CoA (AcCoA) and maintain oxidative phosphorylation. More so than glycolysis, FAO increases NADH/NAD+ and AcCoA/coenzyme A ratios as well as cytoplasmic citrate thereby inhibiting pyruvate dehydrogenase (PDH), phosphofructokinase, hexokinase (HK), and glucose uptake (284–286). By contrast, glucose utilization by the TCA cycle tends to produce a greater buildup of citrate-derived, cytoplasmic coenzyme A (CoA) and malonyl-CoA, which exerts potent negative control over Cpt1.
Figure 5 Co-regulation of glycolysis and FAO. Starvation or glucose deprivation mobilizes lipolytic pathways and upregulates FAO to provide an alternate source of acetyl-CoA (AcCoA) and maintain oxidative phosphorylation. More so than glycolysis, FAO increases NADH/NAD+ and AcCoA/coenzyme A ratios as well as cytoplasmic citrate thereby inhibiting pyruvate dehydrogenase (PDH), phosphofructokinase, hexokinase (HK), and glucose uptake (284–286). By contrast, glucose utilization by the TCA cycle tends to produce a greater buildup of citrate-derived, cytoplasmic coenzyme A (CoA) and malonyl-CoA, which exerts potent negative control over Cpt1.CC BY · PubMed Central
Figure 6 Differential utilization of neutral lipid stores in the absence of pdha1. (A) Oil Red O-stained liver sections from 6- to 8-week-old pdha1 WT and KO mice showing the latter to be nearly devoid of neutral lipid. Each panel is from a different animal. All sections are 40× magnification. (B) Lipid metabolism in the normal [pyruvate dehydrogenase (PDH)-WT] liver where there exists a balance between exogenous lipid uptake, storage, and utilization. The latter consists of direct incorporation of stored lipids into new membranes and FAO. Both of these occur at low levels because they compete with glycolysis to supply acetyl-CoA (AcCoA). The AcCoA derived from glycolysis is used as a substrate for the energy-generating TCA cycle and the energy-depleting synthesis of de novo membrane. (C) Lipid metabolism in PDH KO livers. The activation of FAO provides an alternate source of AcCoA when it cannot otherwise be supplied by glycolysis. Although this route is sufficient to serve as an energy-generating substrate, it is insufficient to allow for de novo fatty acid and sterol synthesis. Thus, stored hepatic lipid is also utilized directly for this purpose. The net result is the depletion of stored neutral lipid reserves.
Figure 6 Differential utilization of neutral lipid stores in the absence of pdha1. (A) Oil Red O-stained liver sections from 6- to 8-week-old pdha1 WT and KO mice showing the latter to be nearly devoid of neutral lipid. Each panel is from a different animal. All sections are 40× magnification. (B) Lipid metabolism in the normal [pyruvate dehydrogenase (PDH)-WT] liver where there exists a balance between exogenous lipid uptake, storage, and utilization. The latter consists of direct incorporation of stored lipids into new membranes and FAO. Both of these occur at low levels because they compete with glycolysis to supply acetyl-CoA (AcCoA). The AcCoA derived from glycolysis is used as a substrate for the energy-generating TCA cycle and the energy-depleting synthesis of de novo membrane. (C) Lipid metabolism in PDH KO livers. The activation of FAO provides an alternate source of AcCoA when it cannot otherwise be supplied by glycolysis. Although this route is sufficient to serve as an energy-generating substrate, it is insufficient to allow for de novo fatty acid and sterol synthesis. Thus, stored hepatic lipid is also utilized directly for this purpose. The net result is the depletion of stored neutral lipid reserves.CC BY · PubMed Central

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Metadata

Authors
Goetzman, E. S., & Prochownik, E. V.
Affiliations
  • Children's Hospital of Pittsburgh (US)
  • University of Pittsburgh (US)
Corresponding author
Prochownik, Edward V.
ORCID
Venue
Frontiers in Endocrinology
Publisher
Frontiers Media SA
Published
2018-04-12
Volume
9
Pages
129-129
ISSN
1664-2392 (ISSN-L)
DOI
10.3389/fendo.2018.00129
PMC
PMC5907532
OpenAlex
W2797261189
Cited by
199
References
309
Citations by year
2026: 14 · 2025: 20 · 2024: 28 · 2023: 23 · 2022: 33 · 2021: 26 · 2020: 32 · 2019: 17 · 2018: 6
FWCI
2.10
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Endocrinology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institutes of Health (CA174713, DK090242)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Keywords
c-Myc, cancer metabolism, glycolysis, oxidative phosphorylation, glutaminolysis, fatty acid metabolism, tumor cell proliferation, metabolic reprogramming, tumor evolution, metabolic plasticity

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