Inhibition of lactate transport and glycolysis in Ehrlich ascites tumor cells by bioflavonoids

Belt, Judith A.; Thomas, John A.; Buchsbaum, Robert; Racker, Efraim

doi:10.1021/bi00583a011

Cited by 123 publications

(74 citation statements)

References 18 publications

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“…Conversely, as shown in the WiDr model, the relative expression or activity of MCT1 in vitro had no prognostic value for therapeutic gain in vivo, most probably because the onset of metabolic symbiosis is under the control of microenvironmental influences. Finally, a number of reports have attributed to MCT1 a role in lactate efflux in tumor cells with active aerobic glycolysis (33,(38)(39)(40)(41). These studies showed further evidence of lethal intracellular acidification upon MCT1 inhibition in vitro.…”

Section: Figurementioning

confidence: 86%

Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice

Sonveaux¹,

Végran²,

Schroeder³

et al. 2008

J. Clin. Invest.

1,109

1,561

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Tumors contain oxygenated and hypoxic regions, so the tumor cell population is heterogeneous. Hypoxic tumor cells primarily use glucose for glycolytic energy production and release lactic acid, creating a lactate gradient that mirrors the oxygen gradient in the tumor. By contrast, oxygenated tumor cells have been thought to primarily use glucose for oxidative energy production. Although lactate is generally considered a waste product, we now show that it is a prominent substrate that fuels the oxidative metabolism of oxygenated tumor cells. There is therefore a symbiosis in which glycolytic and oxidative tumor cells mutually regulate their access to energy metabolites. We identified monocarboxylate transporter 1 (MCT1) as the prominent path for lactate uptake by a human cervix squamous carcinoma cell line that preferentially utilized lactate for oxidative metabolism. Inhibiting MCT1 with α-cyano-4-hydroxycinnamate (CHC) or siRNA in these cells induced a switch from lactate-fueled respiration to glycolysis. A similar switch from lactate-fueled respiration to glycolysis by oxygenated tumor cells in both a mouse model of lung carcinoma and xenotransplanted human colorectal adenocarcinoma cells was observed after administration of CHC. This retarded tumor growth, as the hypoxic/glycolytic tumor cells died from glucose starvation, and rendered the remaining cells sensitive to irradiation. As MCT1 was found to be expressed by an array of primary human tumors, we suggest that MCT1 inhibition has clinical antitumor potential.

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Section: Figurementioning

confidence: 86%

Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice

Sonveaux¹,

Végran²,

Schroeder³

et al. 2008

J. Clin. Invest.

1,109

1,561

View full text Add to dashboard Cite

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“…All three MCT blockers that were tested reduced CAP recovery after a 60 min period of glucose withdrawal. Quercetin preferentially inhibits lactate efflux from cells (Belt et al, 1979) (see also McKenna et al, 1998). When 20 mM lactate was added to the glucose-free perfusate, quercetin had no effect on the CAP (see Fig.…”

Section: Discussionmentioning

confidence: 96%

“…We first tested the bioflavonoid quercetin, which preferentially blocks extrusion of lactate (Belt et al, 1979; Volk et al, Figure 4. Effect of nerve glycogen content on axon function during, and recovery from, a 60 min period of glucose deprivation.…”

Section: Blockade Of Lactate Transport and Axon Function During Glucomentioning

confidence: 99%

Astrocytic Glycogen Influences Axon Function and Survival during Glucose Deprivation in Central White Matter

Wender

Brown²,

Fern³

et al. 2000

J. Neurosci.

344

339

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We tested the hypothesis that astrocytic glycogen sustains axon function during and enhances axon survival after 60 min of glucose deprivation. Axon function in the rat optic nerve (RON), a CNS white matter tract, was monitored by measuring the area of the stimulus-evoked compound action potential (CAP). Switching to glucose-free artificial CSF (aCSF) had no effect on the CAP area for ϳ30 min, after which the CAP rapidly failed. Exposure to glucose-free aCSF for 60 min caused irreversible injury, which was measured as incomplete recovery of the CAP. Glycogen content of the RON fell to a low stable level 30 min after glucose withdrawal, compatible with rapid use in the absence of glucose. An increase of glycogen content induced by high-glucose pretreatment increased the latency to CAP failure and improved CAP recovery. Conversely, a decrease of glycogen content induced by norepinephrine pretreatment decreased the latency to CAP failure and reduced CAP recovery. To determine whether lactate represented the fuel derived from glycogen and shuttled to axons, we used the lactate transport blockers quercetin, ␣-cyano-4-hydroxycinnamic acid (4-CIN), and p-chloromercuribenzene sulfonic acid ( pCMBS). All transport blockers, when applied during glucose withdrawal, decreased latency to CAP failure and decreased CAP recovery. The inhibitors 4-CIN and pCMBS, but not quercetin, blocked lactate uptake by axons. These results indicated that, in the absence of glucose, astrocytic glycogen was broken down to lactate, which was transferred to axons for fuel. Key words: astrocytes; ␣-cyano-4-hydroxycinnamate; glucose; hypoglycemia; lactate; p-chloromercuribenzene sulfonic acid; quercetin; rat optic nerveThe function of brain glycogen is not well understood. Glycogen turns over rapidly in the brain, however, and turnover is enhanced when adjacent neural activity is increased (Orkand et al., 1973;Pentreath and Kai-Kai, 1982;Swanson et al., 1992). It is appealing to imagine that glycogen might serve to provide fuel to the brain when glucose is in short supply. Indeed, astrocytic glycogen in vitro is degraded rapidly when glucose is withdrawn (Dringen et al., 1993), and glycogen falls rapidly in vivo during ischemia, with a time course that is closely related to the depletion of ATP and the accumulation of lactate (Swanson et al., 1989a). These observations are consistent with the action of glycogen as a fuel source during glucose shortage, but they do not prove this hypothesis. Glycogen content varies by a factor of two or more between brain regions [it is highest in the brainstem and cerebellum and lowest in the striatum and white matter (Swanson et al., 1989a)]. Energy metabolism also varies significantly between different brain regions (Sokoloff et al., 1977). Therefore, glycogen could be more protective against glucose depletion in some areas than in others.Given all of the above, it is natural to wonder whether glycogen can enhance the survival and function of brain tissue in the absence of glucose. Surprisingly, only a single st...

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“…First, we determined the intracellular concentration of lactate, the product of the generation of ATP via the anaerobic catabolism of glucose. The intracellular accumulation of lactate can lead to the inhibition of glycolysis (28), as such heat shock could affect oxidative phosphorylation via the inhibition of glyolysis by FIGURE 4. Hyperthermia preserved association of Hsp90 and eNOS even in hyperglycemia.…”

Section: Increased Hsp90⅐enos Interactions In Heat-shocked Cells and mentioning

confidence: 99%

Hyperthermia-induced Hsp90·eNOS Preserves Mitochondrial Respiration in Hyperglycemic Endothelial Cells by Down-regulating Glut-1 and Up-regulating G6PD Activity

Presley

Vedam

Druhan

et al. 2010

Journal of Biological Chemistry

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Uncoupling of NO production from NADPH oxidation by endothelial nitric-oxide synthase (eNOS) is enhanced in hyperglycemic endothelium, potentially due to dissociation of heat shock proteins 90 (Hsp90), and cellular glucose homeostasis is enhanced by a ROS-induced positive feed back mechanism. In this study we investigated how such an uncoupling impacts oxygen metabolism and how the oxidative phosphorylation can be preserved by heat shock (42°C for 2 h, hyperthermia) in bovine aortic endothelial cells. Normal and heat-shocked bovine aortic endothelial cells were exposed to normoglycemia (NG, 5.0 mM) or hyperglycemia (30 mM). With hyperglycemia treatment, O 2 consumption rate was reduced (from V O 2 max ‫؍‬ 7.51 ؎ 0.54 to 2.35 ؎ 0.27 mm Hg/min/10 6 cells), whereas in heat-shocked cells, O 2 consumption rate remained unaltered (8.19 ؎ 1.01 mm Hg/min/10 ؋ 10 6 cells). Heat shock was found to enhance Hsp90/endothelial NOS interactions and produce higher NO. Moreover, ROS generation in the hyperglycemic condition was also reduced in heat-shocked cells. Interestingly, glucose uptake was reduced in heat-shocked cells as a result of decrease in Glut-1 protein level. Glucose phosphate dehydrogenase activity that gives rise to NADPH generation was increased by hyperthermia, and mitochondrial oxidative metabolism was preserved. In conclusion, the present study provides a novel mechanism wherein the reduced oxidative stress in heat-shocked hyperglycemic cells down-regulates Glut-1 and glucose uptake, and fine-tuning of this pathway may be a potential approach to use for therapeutic benefit of diabetes mellitus. Heat shock proteins (Hsps)2 play critical roles in endothelial function in the hyperglycemic state, although their exact function is not clearly established. Along with hyperglycemia, the production of superoxide, insulin resistance, and a decline in vascular bioavailability of nitric oxide (NO) contribute to extreme rates of morbidity and mortality (1-4). Various factors regulate endothelial nitric-oxide synthase (eNOS) signaling in endothelial cells by modulating its phosphorylation/de-phosphorylation dynamics and the coupling/uncoupling of its redox reactions. Protein kinase B (Akt) phosphorylates eNOS on serine 1177 and increases the production of NO (5), and it is found to be very critical in overall glucose metabolism and cell survival (6). Hsp90 binding to eNOS was found to be a prerequisite for successive Akt-mediated stimulation of eNOS, and indeed, Hsp90 can be considered as a scaffold between eNOS and Akt (5,7,8). Vascular endothelial growth factor enhances the recruitment of Hsp90 and facilitates Akt-dependent phosphorylation of eNOS, which results in increased NO production. NO generation is reduced under diabetic conditions due to NOS uncoupling (i.e. incomplete redox transformation of NADPH, arginine, and O 2 to NO, citrulline, and H 2 O, leading instead to the generation of reactive oxygen species) resulting in the generation of more superoxide, and Hsp levels, especially Hsp90, are reduced in hypergly...

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Inhibition of lactate transport and glycolysis in Ehrlich ascites tumor cells by bioflavonoids

Cited by 123 publications

References 18 publications

Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice

Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice

Astrocytic Glycogen Influences Axon Function and Survival during Glucose Deprivation in Central White Matter

Hyperthermia-induced Hsp90·eNOS Preserves Mitochondrial Respiration in Hyperglycemic Endothelial Cells by Down-regulating Glut-1 and Up-regulating G6PD Activity

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