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Review
. 2012 May 1;26(9):877-90.
doi: 10.1101/gad.189365.112.

Links between metabolism and cancer

Chi V Dang  1
Affiliations
Review

Links between metabolism and cancer

Chi V Dang. Genes Dev. .

Abstract

Metabolism generates oxygen radicals, which contribute to oncogenic mutations. Activated oncogenes and loss of tumor suppressors in turn alter metabolism and induce aerobic glycolysis. Aerobic glycolysis or the Warburg effect links the high rate of glucose fermentation to cancer. Together with glutamine, glucose via glycolysis provides the carbon skeletons, NADPH, and ATP to build new cancer cells, which persist in hypoxia that in turn rewires metabolic pathways for cell growth and survival. Excessive caloric intake is associated with an increased risk for cancers, while caloric restriction is protective, perhaps through clearance of mitochondria or mitophagy, thereby reducing oxidative stress. Hence, the links between metabolism and cancer are multifaceted, spanning from the low incidence of cancer in large mammals with low specific metabolic rates to altered cancer cell metabolism resulting from mutated enzymes or cancer genes.

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Figures

Figure 1.
Figure 1.
Glucose and glutamine feed cell growth and proliferation. Glucose and glutamine are depicted to contribute to glycolysis (conversion of glucose to pyruvate) and the TCA cycle, which is shown as a hybrid cycle comprising glucose and glutamine carbons. Carbon skeletons from glycolysis and the TCA cycle contribute to macromolecular synthesis for the growing cell.
Figure 2.
Figure 2.
Hypoxic rewiring of metabolism. While aerobic proliferating cells use glucose and glutamine for biomass production through the TCA cycle, hypoxic cells shunt glucose to lactate and rewire glutamine metabolism. Glutamine can be used to drive the TCA cycle independently of glucose or contribute to lipid synthesis via IDH-mediated reductive carboxylation of ketoglutarate generated from glutamine.
Figure 3.
Figure 3.
Nutrient signaling for biomass accumulation. (A) Yeasts could transmit nutrient sensing to biomass accumulation without specific growth factors. (B) A large fraction of cellular mass comprises ribosomes that accumulate in the G1- to S-phase period of the cell cycle. (C) Mammalian cells at rest use nutrients to maintain structure and homeostasis of membrane potentials. Upon stimulation with growth factors, signals from nutrients and growth factor receptors are integrated (via an AND logic gate) to stimulate cell growth or biomass accumulation.
Figure 4.
Figure 4.
Nutrient sensing and yeast cell growth. Glucose and glutamine are depicted to signal via Ras and TORC1, respectively, to inhibit repressors (Dot6 and Tod6) of ribosomal biogenesis (Ribi) genes.
Figure 5.
Figure 5.
Mammalian cell growth requires growth factors and nutrients. Glucose is shown to signal to MondoA, which down-modulates glucose metabolism. Glutamine contributes to mTORC1 activation through import of leucine and production of GTP via the TCA cycle. GTP is required for mTORC1 activation by its association with lysosomal membranes. mTORC1 activation of S6K1 stimulates ribosome biogenesis (Ribi) genes. Growth factor signaling through receptor tyrosine kinase (RTK) activates PI3K and mTORC2, resulting in AKT activation that stimulates glucose metabolism. Signal transduction via MEK to MYC initiates a transcriptional program that stimulates Ribi genes, coupled with increased glucose and glutamine metabolic gene expression.
Figure 6.
Figure 6.
(A) Diagram depicting clonal expansion of cancer cells after a hypothetical mutational event. (B) This cartoon illustrates the significantly different number of cell divisions needed to produce an adult elephant versus a mouse from similar-sized embryos. (C) Empirical measurements of specific metabolic rates (energy in watts per gram of tissue) reveal a power law relation with body mass (grams) as illustrated by a linear log–log relation (dashed line). Cartoons of the mouse and elephant are placed over the approximate body mass. Note the significant difference in specific metabolic rates (several orders of magnitude) between the mouse and elephant (see Savage et al. 2007 for details).
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