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The engine driving the ship: metabolic steering of cell proliferation and death

Nature Reviews Molecular Cell Biology volume 11, pages 715–727 (2010)Cite this article

Subjects

Key Points

  • Metabolic pathways such as glycolysis, the tricarboxylic acid cycle and fatty acid synthesis influence key cell cycle and apoptotic effectors to promote cell survival or death and dictate cell fate.

  • 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase isoenzyme 3 (PFKFB3) produces fructose-2,6-bisphosphate and promotes the expression of cyclin D3 and Cdc25C while inhibiting the expression of the cyclin-dependent kinase 1 (CDK1) inhibitor p27. In a reciprocal manner, cyclin D1 overexpression results in decreased expression of hexokinase II, pyruvate kinase, fatty acid synthase and acetyl-CoA carboxylase, thus influencing metabolism.

  • The anaphase-promoting complex–Cdc20 homologue 1 (APC–CDH1) is active from late mitosis and throughout G1 phase and has been shown to ubiquitylate PFKFB3, targeting it for degradation. APC–CDH1 activity results in decreased PFKFB3 levels, decreased glycolysis and a concomitant increase in glucose flux through the pentose phosphate pathway (PPP) to protect cells from oxidative stress-induced apoptosis.

  • ATP-citrate lyase (ACL) links glucose metabolism to replication and transcription by regulating citrate-derived acetyl-CoA. Glucose metabolism results in increased citrate production, which is used by ACL to generate acetyl-CoA, a substrate important for histone acetylation and the transcriptional upregulation of genes, including those involved in metabolism such as phosphofructokinase 1, hexokinase II, L-lactate dehydrogenase A chain and glucose transporter 4.

  • When intracellular glucose levels are low, p53 is phosphorylated by 5′-AMP-activated protein kinase (AMPK) to promote G1–S cell cycle arrest. p53 activity also influences apoptosis by regulating the expression of PUMA, NOXA, BAX and PIDD, and metabolism by regulating the expression of guanidinoacetate N-methyltransferase (GAMT), synthesis of cytochrome c oxidase 2 (SCO2), glutaminase 2, TP53-induced glycolysis and apoptosis regulator (TIGAR) and phosphoglycerate mutase (PGM).

  • In Xenopus laevis, caspase 2 is inhibited in response to glucose flux through the PPP and NADPH production, through phosphorylation mediated by metabolism-regulated Ca2+/calmodulin-dependent protein kinase II. Caspase 2 activation is also under metabolic control, as waning NADPH levels signal for 14-3-3 release from caspase 2, facilitating caspase 2 dephosphorylation by protein phosphatase 1. B cell lymphoma 2 (BCL-2) family proteins are extensively regulated by metabolism to create a threshold for mitochondrial outer membrane permeabilization and apoptosis. For example, pro-apoptotic BCL-2 antagonist of cell death (BAD) is phosphorylated and inhibited by AKT in response to increased glucose uptake; this prevents BAD-mediated apoptosis in the setting of sufficient nutrients and raises the threshold for apoptotic stimuli.

Abstract

Metabolic activity is a crucial determinant of a cell's decision to proliferate or die. Although it is not fully understood how metabolic pathways such as glycolysis and the pentose phosphate pathway communicate to cell cycle and apoptotic effectors, it is clear that a complex network of signalling molecules is required to integrate metabolic inputs. D-type cyclins, cyclin-dependent kinases, the anaphase-promoting complex, p53, caspase 2 and B cell lymphoma 2 proteins, among others, have been shown to be regulated by metabolic crosstalk. Elucidating these pathways is of great importance, as metabolic aberrations and their downstream effects are known to contribute to the aetiology of cancer and degenerative disorders.

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Figure 1: Overview of metabolism.
Figure 2: Crosstalk between cell cycle transitions and metabolism.
Figure 3: p53 activation and its effects on metabolism and cellular fate.
Figure 4: Metabolic regulation of caspase 2.

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We are grateful to J. Rathmell and M. Kurokawa for critical reading and feedback on the manuscript

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    Marisa R. Buchakjian & Sally Kornbluth

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Glossary

Pentose phosphate pathway

A metabolic pathway that generates NADPH and pentose sugars from glucose-6-phosphate. NADPH is important for the biosynthesis of many cell components and serves as a major cellular antioxidant.

Anaphase-promoting complex

A large multisubunit E3 ubiquitin ligase with a RING-containing subunit (APC11) that ubiquitylates, among other proteins, several proteins that are crucial for the transition from M phase to G1.

Initiator caspase

A caspase lying at the apex of apoptotic signalling cascades (for example, caspase 2, caspase 8 and caspase 9). These cleave and activate executioner caspases.

Executioner caspase

A caspase (caspase 3, caspase 6 and caspase 7) that cleaves a range of cellular substrate proteins, resulting in apoptotic cell death. Also termed effector caspases.

Senescence

A cellular state of prolonged G1 cell cycle arrest with characteristic metabolic, morphological and protein expression alterations.

Bimolecular fluorescence complementation

A method for detecting protein–protein interactions using non-fluorescent protein halves fused to the proteins of interest. When the proteins of interest interact, the non-fluorescent halves associate to form a fluorescent complex.

Autophagy

A process in which intracellular contents are destroyed by bulk enclosure of cytoplasmic material in membrane-enclosed vesicles that are then targeted for lysosomal degradation.

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Buchakjian, M., Kornbluth, S. The engine driving the ship: metabolic steering of cell proliferation and death. Nat Rev Mol Cell Biol 11, 715–727 (2010). https://doi.org/10.1038/nrm2972

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