Metabolic regulation of T lymphocytes MacIver, Nancie J; Michalek, Ryan D; Rathmell, Jeffrey C
Annual review of immunology,
01/2013, Volume:
31
Journal Article
Peer reviewed
Open access
T cell activation leads to dramatic shifts in cell metabolism to protect against pathogens and to orchestrate the action of other immune cells. Quiescent T cells require predominantly ATP-generating ...processes, whereas proliferating effector T cells require high metabolic flux through growth-promoting pathways. Further, functionally distinct T cell subsets require distinct energetic and biosynthetic pathways to support their specific functional needs. Pathways that control immune cell function and metabolism are intimately linked, and changes in cell metabolism at both the cell and system levels have been shown to enhance or suppress specific T cell functions. As a result of these findings, cell metabolism is now appreciated as a key regulator of T cell function specification and fate. This review discusses the role of cellular metabolism in T cell development, activation, differentiation, and function to highlight the clinical relevance and opportunities for therapeutic interventions that may be used to disrupt immune pathogenesis.
Increased glucose metabolism and reprogramming toward aerobic glycolysis are a hallmark of cancer cells, meeting their metabolic needs for sustained cell proliferation. Metabolic reprogramming is ...usually considered as a downstream consequence of tumor development and oncogene activation; growing evidence indicates, however, that metabolism on its turn can support oncogenic signaling to foster tumor malignancy. Here, we explored how glucose metabolism regulates gene transcription and found an unexpected link with YAP/TAZ, key transcription factors regulating organ growth, tumor cell proliferation and aggressiveness. When cells actively incorporate glucose and route it through glycolysis, YAP/TAZ are fully active; when glucose metabolism is blocked, or glycolysis is reduced, YAP/TAZ transcriptional activity is decreased. Accordingly, glycolysis is required to sustain YAP/TAZ pro‐tumorigenic functions, and YAP/TAZ are required for the full deployment of glucose growth‐promoting activity. Mechanistically we found that phosphofructokinase (PFK1), the enzyme regulating the first committed step of glycolysis, binds the YAP/TAZ transcriptional cofactors TEADs and promotes their functional and biochemical cooperation with YAP/TAZ. Strikingly, this regulation is conserved in Drosophila, where phosphofructokinase is required for tissue overgrowth promoted by Yki, the fly homologue of YAP. Moreover, gene expression regulated by glucose metabolism in breast cancer cells is strongly associated in a large dataset of primary human mammary tumors with YAP/TAZ activation and with the progression toward more advanced and malignant stages. These findings suggest that aerobic glycolysis endows cancer cells with particular metabolic properties and at the same time sustains transcription factors with potent pro‐tumorigenic activities such as YAP/TAZ.
Synopsis
The direct binding of Phosphofructokinase‐1 with TEAD transcription factors in breast cancer cells unravels a new molecular link between cancer cell metabolism and YAP/TAZ‐mediated gene regulation.
YAP/TAZ transcriptional activity is regulated by glucose metabolism and glycolysis.
Glycolysis modulates YAP/TAZ interaction with TEAD transcription factors.
Glycolysis intersects YAP/TAZ activity to regulate cancer cell proliferation and tissue overgrowth.
The direct binding of Phosphofructokinase‐1 with TEAD transcription factors in breast cancer cells unravels a new molecular link between cancer cell metabolism and YAP/TAZ‐mediated gene regulation.
Studying the metabolism of immune cells in recent years has emphasized the tight link existing between the metabolic state and the phenotype of these cells. Macrophages in particular are a good ...example of this phenomenon. Whether the macrophage obtains its energy through glycolysis or through oxidative metabolism can give rise to different phenotypes. Classically activated or M1 macrophages are key players of the first line of defense against bacterial infections and are known to obtain energy through glycolysis. Alternatively activated or M2 macrophages on the other hand, are involved in tissue repair and wound healing and use oxidative metabolism to fuel their longer-term functions. Metabolic intermediates however, are not just a source of energy but can be directly implicated in a particular macrophage phenotype. In M1 macrophages, the Krebs cycle intermediate succinate regulates HIF1α, which is responsible for driving the sustained production of the pro-inflammatory cytokine IL1β. In M2 macrophages, the sedoheptulose kinase CARKL is critical for regulating the pentose phosphate pathway. The potential to target these events and impact on disease is an exciting prospect.
CD8
memory T (Tm) cells are fundamental for protective immunity against infections and cancers
. Metabolic activities are crucial in controlling memory T-cell homeostasis, but mechanisms linking ...metabolic signals to memory formation and survival remain elusive. Here we show that CD8
Tm cells markedly upregulate cytosolic phosphoenolpyruvate carboxykinase (Pck1), the hub molecule regulating glycolysis, tricarboxylic acid cycle and gluconeogenesis, to increase glycogenesis via gluconeogenesis. The resultant glycogen is then channelled to glycogenolysis to generate glucose-6-phosphate and the subsequent pentose phosphate pathway (PPP) that generates abundant NADPH, ensuring high levels of reduced glutathione in Tm cells. Abrogation of Pck1-glycogen-PPP decreases GSH/GSSG ratios and increases levels of reactive oxygen species (ROS), leading to impairment of CD8
Tm formation and maintenance. Importantly, this metabolic regulatory mechanism could be readily translated into more efficient T-cell immunotherapy in mouse tumour models.
Once thought to be a waste product of anaerobic metabolism, lactate is now known to form continuously under aerobic conditions. Shuttling between producer and consumer cells fulfills at least three ...purposes for lactate: (1) a major energy source, (2) the major gluconeogenic precursor, and (3) a signaling molecule. “Lactate shuttle” (LS) concepts describe the roles of lactate in delivery of oxidative and gluconeogenic substrates as well as in cell signaling. In medicine, it has long been recognized that the elevation of blood lactate correlates with illness or injury severity. However, with lactate shuttle theory in mind, some clinicians are now appreciating lactatemia as a “strain” and not a “stress” biomarker. In fact, clinical studies are utilizing lactate to treat pro-inflammatory conditions and to deliver optimal fuel for working muscles in sports medicine. The above, as well as historic and recent studies of lactate metabolism and shuttling, are discussed in the following review.
Though originally thought of as a metabolic waste product and fatigue agent, lactate can now be regarded as the link between glycolytic and aerobic pathways. From its discovery to more recent clinical applications, Brooks provides a comprehensive look at lactate metabolism and shuttling in both basic physiology and medicine.
In this study, we developed a general method to decorate plasmonic gold nanorods (GNRs) with a CD44-targeting functional polymer, containing a hyaluronic acid (HA)-targeting moiety and a small ...molecule Glut1 inhibitor of diclofenac (DC), to obtain GNR/HA-DC. This nanosystem exhibited the superiority of selectively sensitizing tumor cells for photothermal therapy (PTT) by inhibiting anaerobic glycolysis. Upon specifically targeting CD44, sequentially time-dependent DC release could be achieved by the trigger of hyaluronidase (HAase), which abundantly existed in tumor tissues. The released DC depleted the Glut1 level in tumor cells and induced a cascade effect on cellular metabolism by inhibiting glucose uptake, blocking glycolysis, decreasing ATP levels, hampering heat shock protein (HSP) expression, and ultimately leaving malignant cells out from the protection of HSPs to stress (e.g., heat), and then tumor cells were more easy to kill. Owing to the sensitization effect of GNR/HA-DC, CD44 overexpressed tumor cells could be significantly damaged by PTT with an enhanced therapeutic efficiency in vitro and in vivo.
Altered energy metabolism is a biochemical fingerprint of cancer cells that represents one of the "hallmarks of cancer". This metabolic phenotype is characterized by preferential dependence on ...glycolysis (the process of conversion of glucose into pyruvate followed by lactate production) for energy production in an oxygen-independent manner. Although glycolysis is less efficient than oxidative phosphorylation in the net yield of adenosine triphosphate (ATP), cancer cells adapt to this mathematical disadvantage by increased glucose up-take, which in turn facilitates a higher rate of glycolysis. Apart from providing cellular energy, the metabolic intermediates of glycolysis also play a pivotal role in macromolecular biosynthesis, thus conferring selective advantage to cancer cells under diminished nutrient supply. Accumulating data also indicate that intracellular ATP is a critical determinant of chemoresistance. Under hypoxic conditions where glycolysis remains the predominant energy producing pathway sensitizing cancer cells would require intracellular depletion of ATP by inhibition of glycolysis. Together, the oncogenic regulation of glycolysis and multifaceted roles of glycolytic components underscore the biological significance of tumor glycolysis. Thus targeting glycolysis remains attractive for therapeutic intervention. Several preclinical investigations have indeed demonstrated the effectiveness of this therapeutic approach thereby supporting its scientific rationale. Recent reviews have provided a wealth of information on the biochemical targets of glycolysis and their inhibitors. The objective of this review is to present the most recent research on the cancer-specific role of glycolytic enzymes including their non-glycolytic functions in order to explore the potential for therapeutic opportunities. Further, we discuss the translational potential of emerging drug candidates in light of technical advances in treatment modalities such as image-guided targeted delivery of cancer therapeutics.
Metabolic reprogramming plays a critical role in many diseases. A recent study revealed that aerobic glycolysis in lung tissue is closely related to pulmonary fibrosis, and also occurs during ...lipopolysaccharide (LPS)-induced sepsis. However, whether LPS induces aerobic glycolysis in lung fibroblasts remains unknown. The present study demonstrated that LPS promotes collagen synthesis in the lung fibroblasts through aerobic glycolysis via the activation of the PI3K-Akt-mTOR/PFKFB3 pathway. Challenging the human lung fibroblast MRC-5 cell line with LPS activated the PI3K-Akt-mTOR pathway, significantly upregulated the expression of 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3 (PFKFB3), enhanced the aerobic glycolysis, and promoted collagen synthesis. These phenomena could be reversed by the PI3K-Akt inhibitor LY294002, mTOR inhibitor rapamycin, PFKFB3 inhibitor 3PO, or PFKFB3 silencing by specific shRNA, or aerobic glycolysis inhibitor 2-DG. In addition, PFKFB3 expression and aerobic glycolysis were also detected in the mouse model of LPS-induced pulmonary fibrosis, which could be reversed by the intraperitoneal injection of PFKFB3 inhibitor 3PO. Taken together, this study revealed that in LPS-induced pulmonary fibrosis, LPS might mediate lung fibroblast aerobic glycolysis through the activation of the PI3K-Akt-mTOR/PFKFB3 pathway.
Cancer cells undergo metabolic alterations to meet the immense demand for energy, building blocks, and redox potential. Tumors show glucose-avid and lactate-secreting behavior even in the presence of ...oxygen, a process known as aerobic glycolysis. Glycolysis is the backbone of cancer cell metabolism, and cancer cells have evolved various mechanisms to enhance it. Glucose metabolism is intertwined with other metabolic pathways, making cancer metabolism diverse and heterogeneous, where glycolysis plays a central role. Oncogenic signaling accelerates the metabolic activities of glycolytic enzymes, mainly by enhancing their expression or by post-translational modifications. Aerobic glycolysis ferments glucose into lactate which supports tumor growth and metastasis by various mechanisms. Herein, we focused on tumor glycolysis, especially its interactions with the pentose phosphate pathway, glutamine metabolism, one-carbon metabolism, and mitochondrial oxidation. Further, we describe the role and regulation of key glycolytic enzymes in cancer. We summarize the role of lactate, an end product of glycolysis, in tumor growth, and the metabolic adaptations during metastasis. Lastly, we briefly discuss limitations and future directions to improve our understanding of glucose metabolism in cancer.
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