Chapter Twenty‐Two Mechanisms and Methods in Glucose Metabolism and Cell Death

Zhao, Yutong; Wieman, Heather L.; Jacobs, Sarah R.; Rathmell, Jeffrey C.

doi:10.1016/s0076-6879(08)01422-5

Cited by 41 publications

(44 citation statements)

References 50 publications

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“…The regulation of cellular metabolism by different death stimuli in IL-3-dependent cells has been reported previously and the underlying mechanisms may be distinct and complex (14, 25, 28, 33, 34). Genotoxic drugs inhibit both anaerobic and aerobic metabolism in IL-3-dependent cells, probably due to the reduction in expression levels of Glut-1 and several key enzymes involved in glycolytic metabolism, including hexokinase, phophosfructokinase, and pyruvate kinase (33).…”

Section: Discussionmentioning

confidence: 70%

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ER stress modulates cellular metabolism

Wang

Eno

Altman

et al. 2011

Biochemical Journal

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Synopsis Changes in metabolic processes play a critical role in the survival or death of cells subjected to various stresses. Here, we have investigated the effects of endoplasmic reticulum (ER) stress on cellular metabolism. A major difficulty in studying metabolic responses to ER stress is that ER stress normally leads to apoptosis and metabolic changes observed in dying cells may be misleading. Therefore, we have used IL-3-dependent Bak−/− Bax−/− hematopoietic cells which do not die in the presence of the ER stress-inducing drug, tunicamycin. Tunicamycin-treated Bak−/−Bax−/− cells remain viable but cease growth, arresting in G1 and undergoing autophagy in the absence of apoptosis. In these cells we used NMR-based stable isotope resolved metabolomics (SIRM) to determine the metabolic effects of tunicamycin. Glucose was found to be the major carbon source for energy production and anabolic metabolism. Following tunicamycin exposure, glucose uptake and lactate production are greatly reduced. Decreased 13C labeling in several cellular metabolites suggests that mitochondrial function in cells undergoing ER stress is compromised. Consistent with this, mitochondrial membrane potential, oxygen consumption, and cellular ATP level are much lower compared with untreated cells. Importantly, the effects of tunicamycin on cellular metabolic processes may be related to a reduction of cell surface Glut-1 levels which, in turn, may reflect decreased Akt signaling. These results suggest that ER stress exerts profound effects on several central metabolic processes which may help explain cell death arising from ER stress in normal cells.

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Section: Discussionmentioning

confidence: 70%

“…The inhibition of anaerobic metabolism has been reported to lead to compromised mitochondrial function (28). One example is the reduction in glucose utilization caused by growth factor withdrawal in IL-3-dependent cells, which is associated with disruption of mitochondrial function and subsequent apoptosis (29).…”

Section: Discussionmentioning

confidence: 99%

ER stress modulates cellular metabolism

Wang

Eno

Altman

et al. 2011

Biochemical Journal

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“…CD4 T cells also exhibited higher staining with the potentiometric dye TMRE, both ex vivo and after activation. This suggests that in addition to elevated mitochondrial mass, CD4 cells have a greater mitochondrial membrane potential [26] ( Fig. 6B middle ).…”

Section: Resultsmentioning

confidence: 95%

Metabolic Reprogramming towards Aerobic Glycolysis Correlates with Greater Proliferative Ability and Resistance to Metabolic Inhibition in CD8 versus CD4 T Cells

2014

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T lymphocytes (T cells) undergo metabolic reprogramming after activation to provide energy and biosynthetic materials for growth, proliferation and differentiation. Distinct T cell subsets, however, adopt metabolic programs specific to support their needs. As CD4 T cells coordinate adaptive immune responses while CD8 T cells become cytotoxic effectors, we compared activation-induced proliferation and metabolic reprogramming of these subsets. Resting CD4 and CD8 T cells were metabolically similar and used a predominantly oxidative metabolism. Following activation CD8 T cells proliferated more rapidly. Stimulation led both CD4 and CD8 T cells to sharply increase glucose metabolism and adopt aerobic glycolysis as a primary metabolic program. Activated CD4 T cells, however, remained more oxidative and had greater maximal respiratory capacity than activated CD8 T cells. CD4 T cells were also associated with greater levels of ROS and increased mitochondrial content, irrespective of the activation context. CD8 cells were better able, however, to oxidize glutamine as an alternative fuel source. The more glycolytic metabolism of activated CD8 T cells correlated with increased capacity for growth and proliferation, along with reduced sensitivity of cell growth to metabolic inhibition. These specific metabolic programs may promote greater growth and proliferation of CD8 T cells and enhance survival in diverse nutrient conditions.

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“…Immunoblotting analysis was performed as described (41), with the exception of Glut1 western blotting, which was performed using a modified protocol to minimize Glut1 aggregation (50). Antibodies used were: Glut1 (1:5000, kindly provided by Dr. Morris Birnbaum, University of Pennsylvania), Hexokinase-2 (C4G5, 1:1000, Cell Signaling, Beverly, MA) Glut4 (1:1000, Cell Signaling), p-mTOR (p-S2448, 1:1000, Cell Signaling), p-AMPK (p-T172, 1:1000, Cell Signaling), p-S6 (p-S235/236, 1:1000, Cell Signaling), and p-PFK2 (p-S483, 1:1000, Santa Cruz Biotechnology, Santa Cruz, CA).…”

Section: Methodsmentioning

confidence: 99%

Oncogene Pathway Activation in Mammary Tumors Dictates FDG-PET Uptake

et al. 2014

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Increased glucose utilization is a hallmark of human cancer that is used to image tumors clinically. In this widely used application, glucose uptake by tumors is monitored by positron emission tomography (PET) of the labeled glucose analog F-18-2-fluoro-2-deoxyglucose (18F-FDG). Despite its widespread clinical use, the cellular and molecular mechanisms that determine FDG uptake - a tool that can monitor tumor heterogeneity - remain poorly understood. In this study, we compared FDG uptake in mammary tumors driven by the Akt1, c-MYC, HER2/neu, Wnt1 or H-Ras oncogenes in genetically engineered mice, correlating it to tumor growth, cell proliferation and levels of gene expression involved in key steps of glycolytic metabolism. We found that FDG uptake by tumors was dictated principally by the driver oncogene and was not independently associated with tumor growth or cellular proliferation. Oncogene downregulation resulted in a rapid decrease in FDG uptake, preceding effects on tumor regression, irrespective of the baseline level of uptake. FDG uptake correlated positively with expression of hexokinase-2 (HK2) and HIF-1α and associated negatively with PFK-2b expression and p-AMPK. The correlation of HK2 and FDG uptake was independent of all variables tested, including the initiating oncogene, suggesting that HK2 is an independent predictor of FDG uptake. In contrast, expression of Glut1 was correlated with FDG uptake only in tumors driven by Akt or HER2/neu. Together, these results showed that the oncogenic pathway activated within a tumor is a primary determinant of its FDG uptake, mediated by key glycolytic enzymes that provide a framework to interpret effects on this key parameter in clinical imaging.

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Chapter Twenty‐Two Mechanisms and Methods in Glucose Metabolism and Cell Death

Cited by 41 publications

References 50 publications

ER stress modulates cellular metabolism

ER stress modulates cellular metabolism

Metabolic Reprogramming towards Aerobic Glycolysis Correlates with Greater Proliferative Ability and Resistance to Metabolic Inhibition in CD8 versus CD4 T Cells

Oncogene Pathway Activation in Mammary Tumors Dictates FDG-PET Uptake

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