Cells overexpressing fructose‐2,6‐bisphosphatase showed enhanced pentose phosphate pathway flux and resistance to oxidative stress

Boada, Jordi; Roig, Teresa; Pérez, Xavier Llopart; Gámez, Antonio; Bartrons, Ramón; Cascante, Marta; Bermúdez, Jordi

doi:10.1016/s0014-5793(00)01950-5

Cited by 51 publications

(29 citation statements)

References 22 publications

(41 reference statements)

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“…This effect was particularly pronounced in the whey + Ca group as indicated by the striking decrease of fructose bisphosphate, the key regulator of gluconeogenesis, and significant decrease of glycolytic intermediates glucose-6-phosphate and fructose-6-phosphate. An increased level of ribose-5-phosphate in the whey + Ca group indicates enhanced flux through pentose phosphate pathway, which is known to be triggered by low concentrations of fructose-2,6-bisphosphate [41] . ER on whey + Ca diet also decreased the level of succinate to the level of lean animals, whereas the level of succinate did not change in the ER control group.…”

Section: Discussionmentioning

confidence: 99%

Metabolomic changes in fatty liver can be modified by dietary protein and calcium during energy restriction

Pilvi¹,

Seppänen‐Laakso²,

Simolin³

et al. 2008

WJG

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AIM:To characterise the effect of energy restriction (ER) on liver lipid and primary metabolite profile by using metabolomic approach. We also investigated whether the effect of energy restriction can be further enhanced by modification of dietary protein source and calcium. METHODS: Liver metabolomic profile of lean and obese C57Bl/6J mice (n = 10/group) were compared with two groups of weight-reduced mice. ER was performed on control diet and whey protein-based high-calcium diet (whey + Ca). The metabolomic analyses were performed using the UPLC/MS based lipidomic platform and the HPLC/MS/MS based primary metabolite platform. RESULTS: ER on both diets significantly reduced hepatic lipid accumulation and lipid droplet size, while only whey + Ca diet significantly decreased blood glucose (P < 0.001) and serum insulin (P < 0.01). In hepatic lipid species the biggest reduction was in the level of triacylglycerols and ceramides while the level of cholesterol esters was significantly increased during ER. Interestingly, diacylglycerol to phospholipid ratio, an indicator of relative amount of diabetogenic diglyceride species, was increased in the control ER group, but decreased in the whey + Ca ER group (P < 0.001, vs obese). ER on whey + Ca diet also totally reversed the obesity induced increase in the relative level of lipotoxic ceramides (P < 0.001, vs obese; P > 0.05, vs lean). These changes were accompanied with up-regulated TCA cycle and pentose phosphate pathway metabolites. CONCLUSION: ER-induced changes on hepatic metabolomic profile can be significantly affected by dietary protein source. The therapeutic potential of whey protein and calcium should be further studied. Pilvi TK, Seppänen-Laakso T, Simolin H, Finckenberg P, Huotari A, Herzig KH, Korpela R, Orešič M, Mervaala EM. Metabolomic changes in fatty liver can be modified by dietary protein and calcium during energy restriction.

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Section: Discussionmentioning

confidence: 99%

Metabolomic changes in fatty liver can be modified by dietary protein and calcium during energy restriction

Pilvi¹,

Seppänen‐Laakso²,

Simolin³

et al. 2008

WJG

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“…2). The pentose phosphate pathway is the first line of defense against oxidative stress in many human cells and can promote the survival of cells during neoplastic transformation and during detachment from extracellular matrix (Boada et al 2000;Debnath et al 2002;Debnath and Brugge 2005;Bensaad et al 2006;Sukhatme and Chan 2012;Hu et al 2013;Kuehne et al 2015).…”

Section: Cancer Cells Undergo Metabolic Changes To Manage Rosmentioning

confidence: 99%

Cancer, Oxidative Stress, and Metastasis

Gill

Piskounova

Morrison

2016

Cold Spring Harb Symp Quant Biol

229

164

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Reactive oxygen species (ROS) are highly reactive molecules that arise from a number of cellular sources, including oxidative metabolism in mitochondria. At low levels they can be advantageous to cells, activating signaling pathways that promote proliferation or survival. At higher levels, ROS can damage or kill cells by oxidizing proteins, lipids, and nucleic acids. It was hypothesized that antioxidants might benefit high-risk patients by reducing the rate of ROS-induced mutations and delaying cancer initiation. However, dietary supplementation with antioxidants has generally proven ineffective or detrimental in clinical trials. High ROS levels limit cancer cell survival during certain windows of cancer initiation and progression. During these periods, dietary supplementation with antioxidants may promote cancer cell survival and cancer progression. This raises the possibility that rather than treating cancer patients with antioxidants, they should be treated with pro-oxidants that exacerbate oxidative stress or block metabolic adaptations that confer oxidative stress resistance.

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“…Total lactate levels in medium may not be a reliable indicator of glycolytic activity, as other sources and pathways (e.g. glutamine and the pentose phosphate pathway) can contribute to lactate formation (26,27). Therefore we examined the direct channeling of fully labeled [ 13 C]glucose to lactate using one-dimensional NMR spectroscopy.…”

Section: Pfkfb3 Mrna Splice Variantmentioning

confidence: 99%

Nuclear Targeting of 6-Phosphofructo-2-kinase (PFKFB3) Increases Proliferation via Cyclin-dependent Kinases

Yalçin

Clem

Simmons

et al. 2009

Journal of Biological Chemistry

196

175

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The regulation of metabolism and growth must be tightly coupled to guarantee the efficient use of energy and anabolic substrates throughout the cell cycle. Fructose 2,6-bisphosphate (Fru-2,6-BP) is an allosteric activator of 6-phosphofructo-1-kinase (PFK-1), a rate-limiting enzyme and essential control point in glycolysis. The concentration of Fru-2,6-BP in mammalian cells is set by four 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (PFKFB1-4), which interconvert fructose 6-phosphate and Fru-2,6-BP. The relative functions of the PFKFB3 and PFKFB4 enzymes are of particular interest because they are activated in human cancers and increased by mitogens and low oxygen. We examined the cellular localization of PFKFB3 and PFKFB4 and unexpectedly found that whereas PFKFB4 localized to the cytoplasm (i.e. the site of glycolysis), PFKFB3 localized to the nucleus. We then overexpressed PFKFB3 and observed no change in glucose metabolism but rather a marked increase in cell proliferation. These effects on proliferation were completely abrogated by mutating either the active site or nuclear localization residues of PFKFB3, demonstrating a requirement for nuclear delivery of Fru-2,6-BP. Using protein array analyses, we then found that ectopic expression of PFKFB3 increased the expression of several key cell cycle proteins, including cyclin-dependent kinase (Cdk)-1, Cdc25C, and cyclin D3 and decreased the expression of the cell cycle inhibitor p27, a universal inhibitor of Cdk-1 and the cell cycle. We also observed that the addition of Fru-2,6-BP to HeLa cell lysates increased the phosphorylation of the Cdk-specific Thr-187 site of p27. Taken together, these observations demonstrate an unexpected role for PFKFB3 in nuclear signaling and indicate that Fru-2,6-BP may couple the activation of glucose metabolism with cell proliferation.Neoplastic transformation and growth require a massive increase in glucose uptake and glycolytic flux not only for energy production but also for the synthesis of nucleic acids, amino acids, and fatty acids. A central control point of glycolysis is the negative allosteric regulation of a rate-limiting enzyme, phosphofructokinase-1 (PFK-1), 2 by ATP (i.e. the Pasteur effect) (1, 2). When intracellular ATP production exceeds usage, ATP inhibits PFK-1 and glycolytic flux. Fructose 2,6-bisphosphate (Fru-2,6-BP) is a potent allosteric activator of PFK-1 that overrides this inhibitory influence of ATP on PFK-1, allowing forward flux of the entire pathway (3-5).The steady-state cellular concentration of Fru-2,6-BP is dependent on the activities of bifunctional 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (PFKFB), which are encoded by four independent genes (PFKFB1-4) (6, 7). The PFKFB3 mRNA is distinguished by the presence of multiple copies of an AUUUA instability motif in its 3Ј-untranslated region and the PFKFB3 protein product has a high kinase:phosphatase activity ratio (740:1) (8). PFKFB3 mRNA is overexpressed by rapidly proliferating transformed cells and the PFKFB3 protein is high...

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Cells overexpressing fructose‐2,6‐bisphosphatase showed enhanced pentose phosphate pathway flux and resistance to oxidative stress

Cited by 51 publications

References 22 publications

Metabolomic changes in fatty liver can be modified by dietary protein and calcium during energy restriction

Metabolomic changes in fatty liver can be modified by dietary protein and calcium during energy restriction

Cancer, Oxidative Stress, and Metastasis

Nuclear Targeting of 6-Phosphofructo-2-kinase (PFKFB3) Increases Proliferation via Cyclin-dependent Kinases

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