Growing tumors face two major metabolic challenges-how to meet the bioenergetic and biosynthetic demands of increased cell proliferation, and how to survive environmental fluctuations in external ...nutrient and oxygen availability when tumor growth outpaces the delivery capabilities of the existing vasculature. Cancer cells display dramatically altered metabolic circuitry that appears to directly result from the oncogenic mutations selected during the tumorigenic process. An emerging theme in cancer biology is that many of the genes that can initiate tumorigenesis are intricately linked to metabolic regulation. In turn, it appears that a number of well-established tumor suppressors play critical roles in suppressing growth and/or proliferation when intracellular supplies of essential metabolites become reduced. In this review, we consider the potential role of tumor suppressors as metabolic regulators.
A “switch” from oxidative phosphorylation (OXPHOS) to aerobic glycolysis is a hallmark of T cell activation and is thought to be required to meet the metabolic demands of proliferation. However, why ...proliferating cells adopt this less efficient metabolism, especially in an oxygen-replete environment, remains incompletely understood. We show here that aerobic glycolysis is specifically required for effector function in T cells but that this pathway is not necessary for proliferation or survival. When activated T cells are provided with costimulation and growth factors but are blocked from engaging glycolysis, their ability to produce IFN-γ is markedly compromised. This defect is translational and is regulated by the binding of the glycolysis enzyme GAPDH to AU-rich elements within the 3′ UTR of IFN-γ mRNA. GAPDH, by engaging/disengaging glycolysis and through fluctuations in its expression, controls effector cytokine production. Thus, aerobic glycolysis is a metabolically regulated signaling mechanism needed to control cellular function.
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•T cells do not require aerobic glycolysis to fuel proliferation or survival•Glycolysis is specifically required for effector cytokine production in T cells•When not engaged in glycolysis, GAPDH binds to cytokine mRNA•Changes in available GAPDH regulate cytokine mRNA translation
Contrary to previous understanding, activated T cells switch from oxidative phosphorylation to aerobic glycolysis not to promote proliferation but instead to augment the production of the antimicrobial protein IFN-γ, which is regulated by the glycolytic enzyme GAPDH.
Metformin is a biguanide widely prescribed to treat Type II diabetes that has gained interest as an antineoplastic agent. Recent work suggests that metformin directly antagonizes cancer cell growth ...through its actions on complex I of the mitochondrial electron transport chain (ETC). However, the mechanisms by which metformin arrests cancer cell proliferation remain poorly defined. Here we demonstrate that the metabolic checkpoint kinases AMP-activated protein kinase (AMPK) and LKB1 are not required for the antiproliferative effects of metformin. Rather, metformin inhibits cancer cell proliferation by suppressing mitochondrial-dependent biosynthetic activity. We show that in vitro metformin decreases the flow of glucose- and glutamine-derived metabolic intermediates into the Tricarboxylic Acid (TCA) cycle, leading to reduced citrate production and de novo lipid biosynthesis. Tumor cells lacking functional mitochondria maintain lipid biosynthesis in the presence of metformin via glutamine-dependent reductive carboxylation, and display reduced sensitivity to metformin-induced proliferative arrest. Our data indicate that metformin inhibits cancer cell proliferation by suppressing the production of mitochondrial-dependent metabolic intermediates required for cell growth, and that metabolic adaptations that bypass mitochondrial-dependent biosynthesis may provide a mechanism of tumor cell resistance to biguanide activity.
AMPK is a metabolic sensor that helps maintain cellular energy homeostasis. Despite evidence linking AMPK with tumor suppressor functions, the role of AMPK in tumorigenesis and tumor metabolism ...is unknown. Here we show that AMPK negatively regulates aerobic glycolysis (the Warburg effect) in cancer cells and suppresses tumor growth in vivo. Genetic ablation of the α1 catalytic subunit of AMPK accelerates Myc-induced lymphomagenesis. Inactivation of AMPKα in both transformed and nontransformed cells promotes a metabolic shift to aerobic glycolysis, increased allocation of glucose carbon into lipids, and biomass accumulation. These metabolic effects require normoxic stabilization of the hypoxia-inducible factor-1α (HIF-1α), as silencing HIF-1α reverses the shift to aerobic glycolysis and the biosynthetic and proliferative advantages conferred by reduced AMPKα signaling. Together our findings suggest that AMPK activity opposes tumor development and that its loss fosters tumor progression in part by regulating cellular metabolic pathways that support cell growth and proliferation.
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► Loss of AMPKα1 cooperates with the Myc oncogene to accelerate lymphomagenesis ► AMPKα dysfunction enhances aerobic glycolysis (Warburg effect) ► Inhibiting HIF-1α reverses the metabolic effects of AMPKα loss ► HIF-1α mediates the growth advantage of tumors with reduced AMPK signaling
Naive T cells undergo metabolic reprogramming to support the increased energetic and biosynthetic demands of effector T cell function. However, how nutrient availability influences T cell metabolism ...and function remains poorly understood. Here we report plasticity in effector T cell metabolism in response to changing nutrient availability. Activated T cells were found to possess a glucose-sensitive metabolic checkpoint controlled by the energy sensor AMP-activated protein kinase (AMPK) that regulated mRNA translation and glutamine-dependent mitochondrial metabolism to maintain T cell bioenergetics and viability. T cells lacking AMPKα1 displayed reduced mitochondrial bioenergetics and cellular ATP in response to glucose limitation in vitro or pathogenic challenge in vivo. Finally, we demonstrated that AMPKα1 is essential for T helper 1 (Th1) and Th17 cell development and primary T cell responses to viral and bacterial infections in vivo. Our data highlight AMPK-dependent regulation of metabolic homeostasis as a key regulator of T cell-mediated adaptive immunity.
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•T cells display metabolic flexibility in response to nutrient limitation•AMPK couples nutrient availability to T cell effector function•T cell metabolic adaptation is AMPKα1-dependent•AMPKα1 is required for primary T cell responses and cellular bioenergetics in vivo
T cells undergo metabolic reprogramming upon activation to fuel T cell growth, proliferation, and effector function. Jones and colleagues show effector T cells adapt their metabolic programs in response to reduced glucose availability, which is regulated by the energy sensor AMPK.
Abstract The AMP-activated protein kinase (AMPK) is a central regulator of cellular metabolism and energy homeostasis in mammalian tissues. Pertinent to cancer biology is the fact that AMPK is ...situated in the center of a signaling network involving established tumor suppressors including LKB1, TSC2 and p53. However, recent research suggests that AMPK can exert pro- or anti-tumorigenic roles in cancer depending on context. Loss of AMPK activity has been observed in several tumor types, and can cooperate with oncogenic drivers to reprogram tumor cell metabolism and enhance cell growth and proliferation. However, AMPK activation can also provide a growth advantage to tumor cells by regulating cellular metabolic plasticity, thus providing tumor cells the flexibility to adapt to metabolic stress. Here we discuss the contextual nature of the “two faces” of AMPK in cancer, and discuss the rationale and context for employing AMPK activators versus inhibitors for cancer therapy.
Remodeling of the tricarboxylic acid (TCA) cycle is a metabolic adaptation accompanying inflammatory macrophage activation. During this process, endogenous metabolites can adopt regulatory roles that ...govern specific aspects of inflammatory response, as recently shown for succinate, which regulates the pro-inflammatory IL-1β-HIF-1α axis. Itaconate is one of the most highly induced metabolites in activated macrophages, yet its functional significance remains unknown. Here, we show that itaconate modulates macrophage metabolism and effector functions by inhibiting succinate dehydrogenase-mediated oxidation of succinate. Through this action, itaconate exerts anti-inflammatory effects when administered in vitro and in vivo during macrophage activation and ischemia-reperfusion injury. Using newly generated Irg1−/− mice, which lack the ability to produce itaconate, we show that endogenous itaconate regulates succinate levels and function, mitochondrial respiration, and inflammatory cytokine production during macrophage activation. These studies highlight itaconate as a major physiological regulator of the global metabolic rewiring and effector functions of inflammatory macrophages.
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•Exogenous itaconate exerts anti-inflammatory effects in vitro and in vivo•Itaconate inhibits Sdh and regulates succinate levels in LPS-activated macrophages•Itaconate controls mitochondrial respiration changes in inflammatory macrophages•Itaconate limits IL-1β, IL-18, IL-6, IL-12, NO, and HIF-1α, but not TNF-α, production
Macrophage activation is accompanied by TCA cycle remodeling, resulting in endogenous metabolites moonlighting as regulatory mediators of the inflammatory response. Lampropoulou et al. investigate the role of itaconate, one of the most highly induced metabolites in activated macrophages, and show that itaconate regulates succinate levels, mitochondrial respiration, and cytokine production.
Reactive oxygen species (ROS) are continuously produced as a by-product of mitochondrial metabolism and eliminated via antioxidant systems. Regulation of mitochondrially produced ROS is required for ...proper cellular function, adaptation to metabolic stress, and bypassing cellular senescence. Here, we report non-canonical regulation of the cellular energy sensor AMP-activated protein kinase (AMPK) by mitochondrial ROS (mROS) that functions to maintain cellular metabolic homeostasis. We demonstrate that mitochondrial ROS are a physiological activator of AMPK and that AMPK activation triggers a PGC-1α-dependent antioxidant response that limits mitochondrial ROS production. Cells lacking AMPK activity display increased mitochondrial ROS levels and undergo premature senescence. Finally, we show that AMPK-PGC-1α-dependent control of mitochondrial ROS regulates HIF-1α stabilization and that mitochondrial ROS promote the Warburg effect in cells lacking AMPK signaling. These data highlight a key function for AMPK in sensing and resolving mitochondrial ROS for stress resistance and maintaining cellular metabolic balance.
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•Mitochondrial ROS (mROS) are a non-canonical activator of AMPK•AMPK-deficient cells have elevated mROS and undergo premature senescence•AMPK activation promotes a PGC-1α-dependent antioxidant response•AMPK-PGC-1α control of mROS regulates Warburg metabolism
AMP-activated protein kinase (AMPK) regulates cellular metabolic balance in response to energy stress. This work by Rabinovitch et al. demonstrates that mitochondrial reactive oxygen species (mROS) are a physiological activator of AMPK and that AMPK couples mROS to an antioxidant program that regulates mitochondrial homeostasis and cellular metabolic balance.
Metabolic reprogramming is a hallmark of cellular transformation, yet little is known about metabolic changes that accompany tumor metastasis. Here we show that primary breast cancer cells display ...extensive metabolic heterogeneity and engage distinct metabolic programs depending on their site of metastasis. Liver-metastatic breast cancer cells exhibit a unique metabolic program compared to bone- or lung-metastatic cells, characterized by increased conversion of glucose-derived pyruvate into lactate and a concomitant reduction in mitochondrial metabolism. Liver-metastatic cells displayed increased HIF-1α activity and expression of the HIF-1α target Pyruvate dehydrogenase kinase-1 (PDK1). Silencing HIF-1α reversed the glycolytic phenotype of liver-metastatic cells, while PDK1 was specifically required for metabolic adaptation to nutrient limitation and hypoxia. Finally, we demonstrate that PDK1 is required for efficient liver metastasis, and its expression is elevated in liver metastases from breast cancer patients. Our data implicate PDK1 as a key regulator of metabolism and metastatic potential in breast cancer.
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•Breast cancer cells display unique metabolic signatures depending on metastatic site•HIF-1α/PDK1 promotes glycolytic metabolism in liver-metastatic breast cancer cells•PDK1 is required for efficient formation of liver metastases•PDK1 expression is elevated in human liver metastases
Dupuy et al. reveal that primary breast cancer cells display extensive metabolic heterogeneity and differentially engage glycolysis or OXPHOS depending on their site of metastasis (liver, lung, or bone). Liver metastases rely on a HIF-1α/PDK1-dependent axis for their intrinsic metabolic reprogramming, which enables their efficient colonization and growth in the liver.
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