SAICAR Stimulates Pyruvate Kinase Isoform M2 and Promotes Cancer Cell Survival in Glucose-Limited Conditions

Keller, Kirstie E.; Tan, Irene S.; Lee, Young‐Sam

doi:10.1126/science.1224409

Cited by 212 publications

(224 citation statements)

References 31 publications

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“…Succinyl-5-aminoimidazole-4-carboxamide-1-ribose-59-phosphate (SAICAR), an intermediate of the de novo purine nucleotide synthesis pathway, also regulates PKM2 activity allosterically and independently of FBP. Cellular SAICAR concentration increases upon glucose starvation, which stimulates PKM2 activity to enhance glucose and glutamine consumption rates, and promotes cancer cell survival (Keller et al, 2012). Thus, allosteric regulation of PKM2 might allow cancer cells to coordinate different metabolic pathways to support cancer cell growth in the often nutrient-limited tumor microenvironment.…”

Section: Regulation Of Pkm2 Expressionmentioning

confidence: 99%

Pyruvate kinase M2 at a glance

Yang

2015

Journal of Cell Science

155

179

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Reprogrammed metabolism is a key feature of cancer cells. The pyruvate kinase M2 (PKM2) isoform, which is commonly upregulated in many human cancers, has been recently shown to play a crucial role in metabolism reprogramming, gene transcription and cell cycle progression. In this Cell Science at a glance article and accompanying poster, we provide a brief overview of recent advances in understanding the mechanisms underlying the regulation of PKM2 expression, enzymatic activity, metabolic functions and subcellular location. We highlight the instrumental role of the non-metabolic functions of PKM2 in tumorigenesis and evaluate the potential to target PKM2 for cancer treatment.

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Section: Regulation Of Pkm2 Expressionmentioning

confidence: 99%

Pyruvate kinase M2 at a glance

Yang

2015

Journal of Cell Science

155

179

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“…Another allosteric activator is succinyl-aminoimidazole-carboxamide-ribose-5-phosphate (SAICAR), which is an intermediate in the purine biosynthetic pathway. Glucose restriction in cancer cells results in accumulation of SAICAR, which activates PKM2, promoting lactate production and cell survival (Keller et al 2012). Thus, PKM2 controls glycolysis and the synthesis of biomolecular building blocks in response to metabolic cues.…”

Section: Metabolic Enzymes That Do Double Duty As Regulators Of Chrommentioning

confidence: 99%

“…PKM2 translocates to the nucleus in response to EGF signaling, interleukin-3, hypoxia, or SAICAR (Hoshino et al 2007;Keller et al 2012;Luo et al 2011;Yang et al 2011). Remarkably, in the nucleus, PKM2 acts as a protein kinase that uses PEP as a phosphate donor instead of ATP (Gao et al 2012;Yang et al 2012).…”

Section: Metabolic Enzymes That Do Double Duty As Regulators Of Chrommentioning

confidence: 99%

Undercover: gene control by metabolites and metabolic enzymes

2016

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To make the appropriate developmental decisions or maintain homeostasis, cells and organisms must coordinate the expression of their genome and metabolic state. However, the molecular mechanisms that relay environmental cues such as nutrient availability to the appropriate gene expression response remain poorly understood. There is a growing awareness that central components of intermediary metabolism are cofactors or cosubstrates of chromatin-modifying enzymes. As such, their concentrations constitute a potential regulatory interface between the metabolic and chromatin states. In addition, there is increasing evidence for a direct involvement of classic metabolic enzymes in gene expression control. These dual-function proteins may provide a direct link between metabolic programing and the control of gene expression. Here, we discuss our current understanding of the molecular mechanisms connecting metabolism to gene expression and their implications for development and disease.Metabolism and gene regulation are two fundamental biological processes that are essential to all living organisms. Homeostasis, cell growth, and differentiation all require the coordination of metabolic state and gene expression programs. Nevertheless, how expression of the genome adapts to metabolic state or environmental changes is not well understood. One level of regulation involves signal transduction pathways that control key transcription factors that act as master regulators of gene expression programs. In addition, post-translational modifications (PTMs) of chromatin play a major role in the activation or repression of gene transcription. These include acetylation, methylation, and phosphorylation of the histones and DNA methylation. Some of these chromatin modifications are involved in the maintenance of stable patterns of gene expression, usually referred to as epigenetic regulation. Pertinently, the activity of enzymes that modulate chromatin is critically dependent on central metabolites as cofactors or cosubstrates. Thus, the availability of metabolites that are required for the activity of histone-modifying enzymes may connect metabolism to chromatin structure and gene expression. Finally, selective metabolic enzymes act in the nucleus to adjust gene transcription in response to changes in metabolic state. Here, we review the interface between metabolism and gene transcription. We focus on the molecular mechanisms involved and discuss unresolved issues and implications for development and disease. The basics of metabolism and gene expression controlMetabolism is the total of all chemical reactions in cells and organisms that maintain life. Metabolism can be divided into two classes: catabolic processes (the breakdown of molecules that usually results in the release of energy) and anabolic processes (the synthesis of components such as proteins, lipids, and nucleic acids, which costs energy). Cellular (or intermediary) metabolism is organized in separate chemical pathways formed by a chain of linked enzymatic reactions in wh...

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“…PKM2 promotes tumor growth (66) by a complex and growing list of activities. First and foremost, PKM2 functions as a pyruvate kinase in glycolysis (Figure 3) but, in contrast to PKM1, its activity is regulated by allosteric interactions with phosphopeptides (67) and intermediary metabolites (68,69) as well as by phosphorylation, acetylation, and oxidation (70)(71)(72). Second, PKM2 functions as a transcriptional coactivator for OCT4, HIF-1α and HIF-2α, and β-catenin (73-75).…”

Section: Figurementioning

confidence: 99%

HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations

Semenza¹

2013

J. Clin. Invest.

1,087

999

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Hypoxia occurs frequently in human cancers and induces adaptive changes in cell metabolism that include a switch from oxidative phosphorylation to glycolysis, increased glycogen synthesis, and a switch from glucose to glutamine as the major substrate for fatty acid synthesis. This broad metabolic reprogramming is coordinated at the transcriptional level by HIF-1, which functions as a master regulator to balance oxygen supply and demand. HIF-1 is also activated in cancer cells by tumor suppressor (e.g., VHL) loss of function and oncogene gain of function (leading to PI3K/AKT/mTOR activity) and mediates metabolic alterations that drive cancer progression and resistance to therapy. Inhibitors of HIF-1 or metabolic enzymes may impair the metabolic flexibility of cancer cells and make them more sensitive to anticancer drugs. IntroductionAll human cells require a constant supply of O 2 to carry out oxidative phosphorylation in the mitochondria for ATP generation. Under hypoxic conditions when O 2 availability is reduced, cells generally respond in three ways: (a) cell proliferation is inhibited to prevent any further increase in the number of O 2 -consuming cells; (b) the rate of oxidative phosphorylation is decreased and the rate of glycolysis is increased in order to decrease O 2 consumption per cell; and (c) the production of angiogenic factors is increased in order to increase O 2 delivery. Mutations in cancer cells dysregulate cell growth and metabolism, but the mechanisms and consequences of this dysregulation vary widely from one cancer to another and even one from cancer cell to another. In some cancer cells, O 2 still regulates the rate of cell proliferation, whereas others continue to divide even under severely hypoxic conditions; some cancers are well vascularized and perfused, whereas most cancers contain steep O 2 gradients that reflect the distance to the nearest blood vessel, the number of intervening cells and their metabolic activity, and the rate at which blood is flowing through the vessel. The metabolism of individual cancer cells reflects the presence of particular genetic alterations, which may alter metabolism in an O 2 -independent manner, as well as the spatial and temporal heterogeneity of O 2 availability within the tumor microenvironment. This Review summarizes the role of HIF-1 in the regulation of cancer cell metabolism, focusing primarily on the use of glucose as a metabolic substrate.

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SAICAR Stimulates Pyruvate Kinase Isoform M2 and Promotes Cancer Cell Survival in Glucose-Limited Conditions

Cited by 212 publications

References 31 publications

Pyruvate kinase M2 at a glance

Pyruvate kinase M2 at a glance

Undercover: gene control by metabolites and metabolic enzymes

HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations

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