The Experts below are selected from a list of 1860 Experts worldwide ranked by ideXlab platform
George A. Brooks - One of the best experts on this subject based on the ideXlab platform.
-
Lactate: link between glycolytic and oxidative metabolism.
Sports Medicine, 2020Co-Authors: George A. BrooksAbstract:Once thought to be the consequence of oxygen lack in contracting skeletal muscle, the glycolytic product Lactate is formed and utilised continuously under fully aerobic conditions. 'Cell-cell' and 'intracellular Lactate Shuttle' concepts describe the roles of Lactate in delivery of oxidative and gluconeogenic substrates as well as in cell signalling. Examples of cell-cell Shuttles include Lactate exchanges (i) between white-glycolytic and red-oxidative fibres within a working muscle bed; (ii) between working skeletal muscle and heart; and (iii) between tissues of net Lactate release and gluconeogenesis. Lactate Shuttles exist in diverse tissues including in the brain, where a Shuttle between astrocytes and neurons is linked to glutamatergic signalling. Because Lactate, the product of glycogenolysis and glycolysis, is disposed of by oxidative metabolism, Lactate shuttling unites the two major processes of cellular energy transduction. Lactate disposal is mainly through oxidation, especially during exercise when oxidation accounts for 70-75% of removal and gluconeogenesis the remainder. Lactate flux occurs down proton and concentration gradients that are established by the mitochondrial Lactate oxidation complex. Marathon running is a power activity requiring high glycolytic and oxidative fluxes; such activities require Lactate shuttling. Knowledge of the Lactate Shuttle is yet to be imparted to the sport.
-
the tortuous path of Lactate Shuttle discovery from cinders and boards to the lab and icu
Journal of Sport and Health Science, 2020Co-Authors: George A. BrooksAbstract:Abstract Once thought to be a waste product of oxygen limited (anaerobic) metabolism, Lactate is now known to form continuously under fully oxygenated (aerobic) conditions. Lactate shuttling between producer (driver) and consumer cells fulfills at least 3 purposes; Lactate is: (1) a major energy source, (2) the major gluconeogenic precursor, and (3) a signaling molecule. The Lactate Shuttle theory is applicable to diverse fields such as sports nutrition and hydration, resuscitation from acidosis and Dengue, treatment of traumatic brain injury, maintenance of glycemia, reduction of inflammation, cardiac support in heart failure and following a myocardial infarction, and to improve cognition. Yet, dysregulated Lactate shuttling disrupts metabolic flexibility, and worse, supports oncogenesis. Lactate production in cancer (the Warburg effect) is involved in all main sequela for carcinogenesis: angiogenesis, immune escape, cell migration, metastasis, and self-sufficient metabolism. The history of the tortuous path of discovery in Lactate metabolism and shuttling was discussed in the 2019 American College of Sports Medicine Joseph B. Wolffe Lecture in Orlando, Florida.
-
the science and translation of Lactate Shuttle theory
Cell Metabolism, 2018Co-Authors: George A. BrooksAbstract: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.
-
Endogenous Nutritive Support after Traumatic Brain Injury: Peripheral Lactate Production for Glucose Supply via Gluconeogenesis
Journal of Neurotrauma, 2015Co-Authors: Thomas C. Glenn, Matthew L Johnson, Michael A Horning, Neil A. Martin, David L. Mcarthur, David A. Hovda, Paul M. Vespa, George A. BrooksAbstract:We evaluated the hypothesis that nutritive needs of injured brains are supported by large and coordinated increases in Lactate shuttling throughout the body. To that end, we used dual isotope tracer ([6,6-(2)H2]glucose, i.e., D2-glucose, and [3-(13)C]Lactate) techniques involving central venous tracer infusion along with cerebral (arterial [art] and jugular bulb [JB]) blood sampling. Patients with traumatic brain injury (TBI) who had nonpenetrating head injuries (n=12, all male) were entered into the study after consent of patients' legal representatives. Written and informed consent was obtained from healthy controls (n=6, including one female). As in previous investigations, the cerebral metabolic rate (CMR) for glucose was suppressed after TBI. Near normal arterial glucose and Lactate levels in patients studied 5.7±2.2 days (range of days 2-10) post-injury, however, belied a 71% increase in systemic Lactate production, compared with control, that was largely cleared by greater (hepatic+renal) glucose production. After TBI, gluconeogenesis from Lactate clearance accounted for 67.1% of glucose rate of appearance (Ra), which was compared with 15.2% in healthy controls. We conclude that elevations in blood glucose concentration after TBI result from a massive mobilization of Lactate from corporeal glycogen reserves. This previously unrecognized mobilization of Lactate subserves hepatic and renal gluconeogenesis. As such, a Lactate Shuttle mechanism indirectly makes substrate available for the body and its essential organs, including the brain, after trauma. In addition, when elevations in arterial Lactate concentration occur after TBI, Lactate shuttling may provide substrate directly to vital organs of the body, including the injured brain.
-
transpulmonary Lactate Shuttle
American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2012Co-Authors: Matthew L Johnson, Chian W Emhoff, Michael A Horning, George A. BrooksAbstract:The shuttling of intermediary metabolites such as Lactate through the vasculature contributes to the dynamic energy and biosynthetic needs of tissues. Tracer kinetic studies offer a powerful tool t...
Bin Cheng - One of the best experts on this subject based on the ideXlab platform.
-
stromal epithelial Lactate Shuttle induced by tumor derived interleukin 1β promotes cell proliferation in oral squamous cell carcinoma
International Journal of Molecular Medicine, 2017Co-Authors: Jie Wu, Yun Hong, Tong Wu, Juan Wang, Xiaobing Chen, Zhi Wang, Bin ChengAbstract:: Stromal-epithelial Lactate Shuttle is an essential process to support fast‑growing tumor cells, however, the underlying mechanism remains ambiguous. Interleukin‑1β (IL‑1β), which is a key node gene in both stromal and epithelial cells of oral squamous cell carcinoma (OSCC), may participate in this metabolic reprogramming. In the present study, anaerobic glycolysis of cancer‑associated fibroblasts (CAFs) was evaluated and the role of IL‑1β in regulating stromal‑epithelial Lactate Shuttle was determined. A co‑culture system of primary fibroblasts and OSCC cell lines (CAL27, UM1 or SCC25) was created to investigate the stromal‑epithelial interaction. α‑smooth muscle actin (α‑SMA) expression of fibroblasts, IL‑1β expression and cell proliferation of OSCC cells, and a series of glycolytic genes were measured. Recombinant IL‑1β treatment and IL‑1β knockdown in UM1 cells were also used to evaluate the effect of IL‑1β. Expression of α‑SMA, glucose transporter 1, hexokinase 2, lactic dehydrogenase and mono‑carboxylate transporter (MCT) 4 were significantly overexpressed in activated fibroblasts, while IL‑1β and MCT1 were upregulated in OSCC cells, indicating enhanced glycolysis in cells of the tumor stroma and a Lactate Shuttle to the tumor cells. Furthermore, exogenous IL‑1β induced fibroblasts to present similar expression profiles as that in the co‑culture system. Silencing of IL‑1β significantly abrogated the regulatory effect of UM1 cells on stromal glycolysis. Additionally, carboxy‑fluorescein succinimidyl ester cell tracing indicated that OSCC cell proliferation was accelerated during co‑cultivation with fibroblasts. These results indicate that tumor‑derived IL‑1β enhanced stromal glycolysis and induced one‑way Lactate flow from the tumor mesenchyme to transformed epithelium, which promotes OSCC proliferation.
-
Stromal-epithelial Lactate Shuttle induced by tumor‑derived interleukin‑1β promotes cell proliferation in oral squamous cell carcinoma.
International Journal of Molecular Medicine, 2017Co-Authors: Jie Wu, Yun Hong, Tong Wu, Juan Wang, Xiaobing Chen, Zhi Wang, Bin ChengAbstract:: Stromal-epithelial Lactate Shuttle is an essential process to support fast‑growing tumor cells, however, the underlying mechanism remains ambiguous. Interleukin‑1β (IL‑1β), which is a key node gene in both stromal and epithelial cells of oral squamous cell carcinoma (OSCC), may participate in this metabolic reprogramming. In the present study, anaerobic glycolysis of cancer‑associated fibroblasts (CAFs) was evaluated and the role of IL‑1β in regulating stromal‑epithelial Lactate Shuttle was determined. A co‑culture system of primary fibroblasts and OSCC cell lines (CAL27, UM1 or SCC25) was created to investigate the stromal‑epithelial interaction. α‑smooth muscle actin (α‑SMA) expression of fibroblasts, IL‑1β expression and cell proliferation of OSCC cells, and a series of glycolytic genes were measured. Recombinant IL‑1β treatment and IL‑1β knockdown in UM1 cells were also used to evaluate the effect of IL‑1β. Expression of α‑SMA, glucose transporter 1, hexokinase 2, lactic dehydrogenase and mono‑carboxylate transporter (MCT) 4 were significantly overexpressed in activated fibroblasts, while IL‑1β and MCT1 were upregulated in OSCC cells, indicating enhanced glycolysis in cells of the tumor stroma and a Lactate Shuttle to the tumor cells. Furthermore, exogenous IL‑1β induced fibroblasts to present similar expression profiles as that in the co‑culture system. Silencing of IL‑1β significantly abrogated the regulatory effect of UM1 cells on stromal glycolysis. Additionally, carboxy‑fluorescein succinimidyl ester cell tracing indicated that OSCC cell proliferation was accelerated during co‑cultivation with fibroblasts. These results indicate that tumor‑derived IL‑1β enhanced stromal glycolysis and induced one‑way Lactate flow from the tumor mesenchyme to transformed epithelium, which promotes OSCC proliferation.
Pierre J Magistretti - One of the best experts on this subject based on the ideXlab platform.
-
genes involved in the astrocyte neuron Lactate Shuttle anls are specifically regulated in cortical astrocytes following sleep deprivation in mice
Sleep, 2013Co-Authors: Jean Marie Petit, Jeanluc Martin, Pierre J Magistretti, J Gyger, Sophie Burletgodinot, Hubert FiumelliAbstract:Study Objectives: There is growing evidence indicating that in order to meet the neuronal energy demands, astrocytes provide Lactate as an energy substrate for neurons through a mechanism called "astrocyte-neuron Lactate Shuttle" (ANLS). Since neuronal activity changes dramatically during vigilance states, we hypothesized that the ANLS may be regulated during the sleep-wake cycle. To test this hypothesis we investigated the expression of genes associated with the ANLS specifically in astrocytes following sleep deprivation. Astrocytes were purified by fluorescence-activated cell sorting from transgenic mice expressing the green fluorescent protein (GFP) under the control of the human astrocytic GFAP-promoter. Design: 6-hour instrumental sleep deprivation (TSD). Setting: Animal sleep research laboratory. Participants: Young (P23-P27) FVB/N-Tg (GFAP-GFP) 14Mes/J (Tg) mice of both sexes and 7-8 week male Tg and FVB/Nj mice. Interventions: Basal sleep recordings and sleep deprivation achieved using a modified cage where animals were gently forced to move. Measurements and Results: Since Tg and FVB/Nj mice displayed a similar sleep-wake pattern, we performed a TSD in young Tg mice. Total RNA was extracted from the GFP-positive and GFP-negative cells sorted from cerebral cortex. Quantitative RT-PCR analysis showed that levels of Glut1, alpha-2-Na/K pump, Glt1, and Ldha mRNAs were significantly increased following TSD in GFP-positive cells. In GFP-negative cells, a tendency to increase, although not significant, was observed for Ldha, Mct2, and alpha-3-Na/K pump mRNAs. Conclusions: This study shows that TSD induces the expression of genes associated with ANLS specifically in astrocytes, underlying the important role of astrocytes in the maintenance of the neuro-metabolic coupling across the sleep-wake cycle.
-
sleep deprivation induces transcriptional modifications of genes related to astrocyte neuron Lactate Shuttle in astrocytes
Glia, 2011Co-Authors: Jean Marie Petit, Jeanluc Martin, J Gyger, Hubert Fiumelli, Pierre J MagistrettiAbstract:Keywords: energy metabolism ; glucose Reference EPFL-CONF-171012View record in Web of Science Record created on 2011-12-16, modified on 2017-05-12
-
Activity-dependent regulation of energy metabolism by astrocytes: an update.
Glia, 2007Co-Authors: Luc Pellerin, Anne-karine Bouzier-sore, Agnès Aubert, S Serres, Michel Merle, Robert Costalat, Pierre J MagistrettiAbstract:Astrocytes play a critical role in the regulation of brain metabolic responses to activity. One detailed mechanism proposed to describe the role of astrocytes in some of these responses has come to be known as the astrocyte-neuron Lactate Shuttle hypothesis (ANLSH). Although controversial, the original concept of a coupling mechanism between neuronal activity and glucose utilization that involves an activation of aerobic glycolysis in astrocytes and Lactate consumption by neurons provides a heuristically valid framework for experimental studies. In this context, it is necessary to provide a survey of recent developments and data pertaining to this model. Thus, here, we review very recent experimental evidence as well as theoretical arguments strongly supporting the original model and in some cases extending it. Aspects revisited include the existence of glutamate-induced glycolysis in astrocytes in vitro, ex vivo, and in vivo, Lactate as a preferential oxidative substrate for neurons, and the notion of net Lactate transfer between astrocytes and neurons in vivo. Inclusion of a role for glycogen in the ANLSH is discussed in the light of a possible extension of the astrocyte-neuron Lactate Shuttle (ANLS) concept rather than as a competing hypothesis. New perspectives offered by the application of this concept include a better understanding of the basis of signals used in functional brain imaging, a role for neuron-glia metabolic interactions in glucose sensing and diabetes, as well as novel strategies to develop therapies against neurodegenerative diseases based upon improving astrocyte-neuron coupled energetics.
-
Dual-Gene, Dual-Cell Type Therapy against an Excitotoxic Insult by Bolstering Neuroenergetics
The Journal of Neuroscience, 2004Co-Authors: Tonya M. Bliss, Luc Pellerin, Pierre J Magistretti, Miranda Ip, Elise Cheng, Masabumi Minami, Robert M. SapolskyAbstract:Increasing evidence suggests that glutamate activates the generation of Lactate from glucose in astrocytes; this Lactate is Shuttled to neurons that use it as a preferential energy source. We explore this multicellular "Lactate Shuttle" with a novel dual-cell, dual-gene therapy approach and determine the neuroprotective potential of enhancing this Shuttle. Viral vector-driven overexpression of a glucose transporter in glia enhanced glucose uptake, Lactate efflux, and the glial capacity to protect neurons from excitotoxicity. In parallel, overexpression of a Lactate transporter in neurons enhanced Lactate uptake and neuronal resistance to excitotoxicity. Finally, overexpression of both transgenes in the respective cell types provided more protection than either therapy alone, demonstrating that a dual-cell, dual-gene therapy approach gives greater neuroprotection than the conventional single-cell, single-gene strategy.
-
evidence supporting the existence of an activity dependent astrocyte neuron Lactate Shuttle
Developmental Neuroscience, 1998Co-Authors: Luc Pellerin, Giovanni Pellegri, Philippe G Bittar, Yves Charnay, Constantin Bouras, Jeanluc Martin, Nephi Stella, Pierre J MagistrettiAbstract:Mounting evidence from in vitro experiments indicates that Lactate is an efficient energy substrate for neurons and that it may significantly contribute to maintain synaptic transmission, particularly during periods of intense activity. Since Lactate does not cross the blood-brain barrier easily, blood-borne Lactate cannot be a significant source. In vitro studies by several laboratories indicate that astrocytes release large amounts of Lactate. In 1994, we proposed a mechanism whereby Lactate could be produced by astrocytes in an activity-dependent, glutamate-mediated manner. Over the last 2 years we have obtained further evidence supporting the notion that a transfer of Lactate from astrocytes to neurons might indeed take place. In this article, we first review data showing the presence of mRNA encoding for two monocarboxylate transporters, MCT1 and MCT2, in the adult mouse brain. Second, by using monoclonal antibodies selectively directed against the two distinct Lactate dehydrogenase isoforms, LDH1 and LDH5, a specific cellular distribution between neurons and astrocytes is revealed which suggests that a population of astrocytes is a Lactate 'source' while neurons may be a Lactate 'sink'. Third, we provide biochemical evidence that Lactate is interchangeable with glucose to support oxidative metabolism in cortical neurons. This set of data is consistent with the existence of an activity-dependent astrocyte-neuron Lactate Shuttle for the supply of energy substrates to neurons.
Gerald A Dienel - One of the best experts on this subject based on the ideXlab platform.
-
lack of appropriate stoichiometry strong evidence against an energetically important astrocyte neuron Lactate Shuttle in brain
Journal of Neuroscience Research, 2017Co-Authors: Gerald A DienelAbstract:: Glutamate-stimulated aerobic glycolysis in astrocytes coupled with Lactate shuttling to neurons where it can be oxidized was proposed as a mechanism to couple excitatory neuronal activity with glucose utilization (CMRglc ) during brain activation. From the outset, this model was not viable because it did not fulfill critical stoichiometric requirements: (i) Calculated glycolytic rates and measured Lactate release rates were discordant in cultured astrocytes. (ii) Lactate oxidation requires oxygen consumption, but the oxygen-glucose index (OGI, calculated as CMRO2 /CMRglc ) fell during activation in human brain, and the small rise in CMRO2 could not fully support oxidation of Lactate produced by disproportionate increases in CMRglc . (iii) Labeled products of glucose metabolism are not retained in activated rat brain, indicating rapid release of a highly labeled, diffusible metabolite identified as Lactate, thereby explaining the CMRglc -CMRO2 mismatch. Additional independent lines of evidence against Lactate shuttling include the following: astrocytic oxidation of glutamate after its uptake can help "pay" for its uptake without stimulating glycolysis; blockade of glutamate receptors during activation in vivo prevents upregulation of metabolism and Lactate release without impairing glutamate uptake; blockade of β-adrenergic receptors prevents the fall in OGI in activated human and rat brain while allowing glutamate uptake; and neurons upregulate glucose utilization in vivo and in vitro under many stimulatory conditions. Studies in immature cultured cells are not appropriate models for Lactate shuttling in adult brain because of their incomplete development of metabolic capability and astrocyte-neuron interactions. Astrocyte-neuron Lactate shuttling does not make large, metabolically significant contributions to energetics of brain activation. © 2017 Wiley Periodicals, Inc.
-
Lack of appropriate stoichiometry: Strong evidence against an energetically important astrocyte–neuron Lactate Shuttle in brain
Journal of Neuroscience Research, 2017Co-Authors: Gerald A DienelAbstract:: Glutamate-stimulated aerobic glycolysis in astrocytes coupled with Lactate shuttling to neurons where it can be oxidized was proposed as a mechanism to couple excitatory neuronal activity with glucose utilization (CMRglc ) during brain activation. From the outset, this model was not viable because it did not fulfill critical stoichiometric requirements: (i) Calculated glycolytic rates and measured Lactate release rates were discordant in cultured astrocytes. (ii) Lactate oxidation requires oxygen consumption, but the oxygen-glucose index (OGI, calculated as CMRO2 /CMRglc ) fell during activation in human brain, and the small rise in CMRO2 could not fully support oxidation of Lactate produced by disproportionate increases in CMRglc . (iii) Labeled products of glucose metabolism are not retained in activated rat brain, indicating rapid release of a highly labeled, diffusible metabolite identified as Lactate, thereby explaining the CMRglc -CMRO2 mismatch. Additional independent lines of evidence against Lactate shuttling include the following: astrocytic oxidation of glutamate after its uptake can help "pay" for its uptake without stimulating glycolysis; blockade of glutamate receptors during activation in vivo prevents upregulation of metabolism and Lactate release without impairing glutamate uptake; blockade of β-adrenergic receptors prevents the fall in OGI in activated human and rat brain while allowing glutamate uptake; and neurons upregulate glucose utilization in vivo and in vitro under many stimulatory conditions. Studies in immature cultured cells are not appropriate models for Lactate shuttling in adult brain because of their incomplete development of metabolic capability and astrocyte-neuron interactions. Astrocyte-neuron Lactate shuttling does not make large, metabolically significant contributions to energetics of brain activation. © 2017 Wiley Periodicals, Inc.
-
Lactate Shuttling and Lactate use as Fuel after Traumatic Brain Injury: Metabolic Considerations:
Journal of Cerebral Blood Flow and Metabolism, 2014Co-Authors: Gerald A DienelAbstract:Lactate is proposed to be generated by astrocytes during glutamatergic neurotransmission and Shuttled to neurons as ‘preferred' oxidative fuel. However, a large body of evidence demonstrates that metabolic changes during activation of living brain disprove essential components of the astrocyte–neuron Lactate Shuttle model. For example, some glutamate is oxidized to generate ATP after its uptake into astrocytes and neuronal glucose phosphorylation rises during activation and provides pyruvate for oxidation. Extension of the notion that Lactate is a preferential fuel into the traumatic brain injury (TBI) field has important clinical implications, and the concept must, therefore, be carefully evaluated before implementation into patient care. Microdialysis studies in TBI patients demonstrate that Lactate and pyruvate levels and Lactate/pyruvate ratios, along with other data, have important diagnostic value to distinguish between ischemia and mitochondrial dysfunction. Results show that Lactate release from human brain to blood predominates over its uptake after TBI, and strong evidence for Lactate metabolism is lacking; mitochondrial dysfunction may inhibit Lactate oxidation. Claims that exogenous Lactate infusion is energetically beneficial for TBI patients are not based on metabolic assays and data are incorrectly interpreted.
-
Nutrition during brain activation: does cell-to-cell Lactate shuttling contribute significantly to sweet and sour food for thought?
Neurochemistry International, 2004Co-Authors: Gerald A Dienel, Nancy F. CruzAbstract:Abstract Functional activation of astrocytic metabolism is believed, according to one hypothesis, to be closely linked to excitatory neurotransmission and to provide Lactate as fuel for oxidative metabolism in neighboring neurons. However, review of emerging evidence suggests that the energetic demands of activated astrocytes are higher and more complex than recognized and much of the Lactate presumably produced by astrocytes is not locally oxidized during activation. In vivo activation studies in normal subjects reveal that the rise in consumption of blood-borne glucose usually exceeds that of oxygen, especially in retina compared to brain. When the contribution of glycogen, the brain’s major energy reserve located in astrocytes, is taken into account the magnitude of the carbohydrate-oxygen utilization mismatch increases further because the magnitude of glycogenolysis greatly exceeds the incremental increase in utilization of blood-borne glucose. Failure of local oxygen consumption to equal that of glucose plus glycogen in vivo is strong evidence against stoichiometric transfer of Lactate from astrocytes to neighboring neurons for oxidation. Thus, astrocytes, not nearby neurons, use the glycogen for energy during physiological activation in normal brain. These findings plus apparent compartmentation of metabolism of glycogen and blood-borne glucose during activation lead to our working hypothesis that activated astrocytes have high energy demands in their fine perisynaptic processes (filopodia) that might be met by glycogenolysis and glycolysis coupled to rapid Lactate clearance. Tissue culture studies do not consistently support the Lactate Shuttle hypothesis because key elements of the model, glutamate-induced increases in glucose utilization and Lactate release, are not observed in many astrocyte preparations, suggesting differences in their oxidative capacities that have not been included in the model. In vivo nutritional interactions between working neurons and astrocytes are not as simple as implied by “sweet (glucose–glycogen) and sour (Lactate) food for thought.”
Jie Wu - One of the best experts on this subject based on the ideXlab platform.
-
stromal epithelial Lactate Shuttle induced by tumor derived interleukin 1β promotes cell proliferation in oral squamous cell carcinoma
International Journal of Molecular Medicine, 2017Co-Authors: Jie Wu, Yun Hong, Tong Wu, Juan Wang, Xiaobing Chen, Zhi Wang, Bin ChengAbstract:: Stromal-epithelial Lactate Shuttle is an essential process to support fast‑growing tumor cells, however, the underlying mechanism remains ambiguous. Interleukin‑1β (IL‑1β), which is a key node gene in both stromal and epithelial cells of oral squamous cell carcinoma (OSCC), may participate in this metabolic reprogramming. In the present study, anaerobic glycolysis of cancer‑associated fibroblasts (CAFs) was evaluated and the role of IL‑1β in regulating stromal‑epithelial Lactate Shuttle was determined. A co‑culture system of primary fibroblasts and OSCC cell lines (CAL27, UM1 or SCC25) was created to investigate the stromal‑epithelial interaction. α‑smooth muscle actin (α‑SMA) expression of fibroblasts, IL‑1β expression and cell proliferation of OSCC cells, and a series of glycolytic genes were measured. Recombinant IL‑1β treatment and IL‑1β knockdown in UM1 cells were also used to evaluate the effect of IL‑1β. Expression of α‑SMA, glucose transporter 1, hexokinase 2, lactic dehydrogenase and mono‑carboxylate transporter (MCT) 4 were significantly overexpressed in activated fibroblasts, while IL‑1β and MCT1 were upregulated in OSCC cells, indicating enhanced glycolysis in cells of the tumor stroma and a Lactate Shuttle to the tumor cells. Furthermore, exogenous IL‑1β induced fibroblasts to present similar expression profiles as that in the co‑culture system. Silencing of IL‑1β significantly abrogated the regulatory effect of UM1 cells on stromal glycolysis. Additionally, carboxy‑fluorescein succinimidyl ester cell tracing indicated that OSCC cell proliferation was accelerated during co‑cultivation with fibroblasts. These results indicate that tumor‑derived IL‑1β enhanced stromal glycolysis and induced one‑way Lactate flow from the tumor mesenchyme to transformed epithelium, which promotes OSCC proliferation.
-
Stromal-epithelial Lactate Shuttle induced by tumor‑derived interleukin‑1β promotes cell proliferation in oral squamous cell carcinoma.
International Journal of Molecular Medicine, 2017Co-Authors: Jie Wu, Yun Hong, Tong Wu, Juan Wang, Xiaobing Chen, Zhi Wang, Bin ChengAbstract:: Stromal-epithelial Lactate Shuttle is an essential process to support fast‑growing tumor cells, however, the underlying mechanism remains ambiguous. Interleukin‑1β (IL‑1β), which is a key node gene in both stromal and epithelial cells of oral squamous cell carcinoma (OSCC), may participate in this metabolic reprogramming. In the present study, anaerobic glycolysis of cancer‑associated fibroblasts (CAFs) was evaluated and the role of IL‑1β in regulating stromal‑epithelial Lactate Shuttle was determined. A co‑culture system of primary fibroblasts and OSCC cell lines (CAL27, UM1 or SCC25) was created to investigate the stromal‑epithelial interaction. α‑smooth muscle actin (α‑SMA) expression of fibroblasts, IL‑1β expression and cell proliferation of OSCC cells, and a series of glycolytic genes were measured. Recombinant IL‑1β treatment and IL‑1β knockdown in UM1 cells were also used to evaluate the effect of IL‑1β. Expression of α‑SMA, glucose transporter 1, hexokinase 2, lactic dehydrogenase and mono‑carboxylate transporter (MCT) 4 were significantly overexpressed in activated fibroblasts, while IL‑1β and MCT1 were upregulated in OSCC cells, indicating enhanced glycolysis in cells of the tumor stroma and a Lactate Shuttle to the tumor cells. Furthermore, exogenous IL‑1β induced fibroblasts to present similar expression profiles as that in the co‑culture system. Silencing of IL‑1β significantly abrogated the regulatory effect of UM1 cells on stromal glycolysis. Additionally, carboxy‑fluorescein succinimidyl ester cell tracing indicated that OSCC cell proliferation was accelerated during co‑cultivation with fibroblasts. These results indicate that tumor‑derived IL‑1β enhanced stromal glycolysis and induced one‑way Lactate flow from the tumor mesenchyme to transformed epithelium, which promotes OSCC proliferation.
