Fuel Economy for Growing Cells: Sophisticated 21st-century analyses of the signaling pathways that control cell growth have led researchers back to the seminal work of Otto Warburg, who discovered in the 1920s that tumor cells generate their energy in an unusual way—by switching from mitochondrial respiration to glycolysis. The advantage conferred by this metabolic switch is puzzling because mitochondrial respiration is a more efficient way to produce ATP. Vander Heiden et al. (p. 1029 ) review arguments that rapidly growing cells have critical metabolic requirements that extend beyond ATP and that a better understanding of these requirements may shed new light on the “Warburg effect” and ultimately lead to new therapies for cancer.

Tumor cell proliferation requires rapid synthesis of macromolecules including lipids, proteins, and nucleotides. Many tumor cells exhibit rapid glucose consumption, with most of the glucose-derived carbon being secreted as lactate despite abundant oxygen availability (the Warburg effect). Here, we used ¹³ C NMR spectroscopy to examine the metabolism of glioblastoma cells exhibiting aerobic glycolysis. In these cells, the tricarboxylic acid (TCA) cycle was active but was characterized by an efflux of substrates for use in biosynthetic pathways, particularly fatty acid synthesis. The success of this synthetic activity depends on activation of pathways to generate reductive power (NADPH) and to restore oxaloacetate for continued TCA cycle function (anaplerosis). Surprisingly, both these needs were met by a high rate of glutamine metabolism. First, conversion of glutamine to lactate (glutaminolysis) was rapid enough to produce sufficient NADPH to support fatty acid synthesis. Second, despite substantial mitochondrial pyruvate metabolism, pyruvate carboxylation was suppressed, and anaplerotic oxaloacetate was derived from glutamine. Glutamine catabolism was accompanied by secretion of alanine and ammonia, such that most of the amino groups from glutamine were lost from the cell rather than incorporated into other molecules. These data demonstrate that transformed cells exhibit a high rate of glutamine consumption that cannot be explained by the nitrogen demand imposed by nucleotide synthesis or maintenance of nonessential amino acid pools. Rather, glutamine metabolism provides a carbon source that facilitates the cell's ability to use glucose-derived carbon and TCA cycle intermediates as biosynthetic precursors.

Chromatin Modifier Modulates Gene Expression: Modification of chromatin structure is usually thought of as a global, relatively nonspecific way of modulating gene expression. However, Wellen et al. (p. 1076 ; see the Perspective by Rathmell and Newgard ) demonstrate that such regulation helps link growth factor–stimulated increases in metabolism to appropriate changes in gene expression. Adenosine triphosphate (ATP)–citrate lyase (ACL), which converts citrate to acetyl–coenzyme A (CoA) in the mitochondria of mammalian cells during metabolism of glucose, was also found to be present in the nucleus, where it might regulate activity of histone acetyl transferases (HATs) by controlling the availability of acetyl-CoA. Indeed, depletion of ACL from cultured human colon carcinoma cells specifically decreased histone acetylation in the nucleus, but appeared not to affect the overall amount of acetylation of proteins in the cells. Loss of ACL in cultured mouse 3T3-L1 cells diminished the increase in histone acetylation normally associated with hormone-stimulated differentiation of these cells and inhibited the increase in expression of specific genes, such as that encoding the Glut4 glucose transporter. Thus, ACL may help cells link metabolic activity to changes in gene expression.

Mammalian cells fuel their growth and proliferation through the catabolism of two main substrates: glucose and glutamine. Most of the remaining metabolites taken up by proliferating cells are not catabolized, but instead are used as building blocks during anabolic macromolecular synthesis. Investigations of phosphoinositol 3-kinase (PI3K) and its downstream effector AKT have confirmed that these oncogenes play a direct role in stimulating glucose uptake and metabolism, rendering the transformed cell addicted to glucose for the maintenance of survival. In contrast, less is known about the regulation of glutamine uptake and metabolism. Here, we report that the transcriptional regulatory properties of the oncogene Myc coordinate the expression of genes necessary for cells to engage in glutamine catabolism that exceeds the cellular requirement for protein and nucleotide biosynthesis. A consequence of this Myc-dependent glutaminolysis is the reprogramming of mitochondrial metabolism to depend on glutamine catabolism to sustain cellular viability and TCA cycle anapleurosis. The ability of Myc-expressing cells to engage in glutaminolysis does not depend on concomitant activation of PI3K or AKT. The stimulation of mitochondrial glutamine metabolism resulted in reduced glucose carbon entering the TCA cycle and a decreased contribution of glucose to the mitochondrial-dependent synthesis of phospholipids. These data suggest that oncogenic levels of Myc induce a transcriptional program that promotes glutaminolysis and triggers cellular addiction to glutamine as a bioenergetic substrate.