The in vitro manipulation of carbohydrate metabolism: a new strategy for deciphering the cellular defence mechanisms against nitric oxide attack

Goffe, Claire Le; Vallette, G.; Jarry, Anne; Bou-Hanna, Chantal; Laboisse, Christian L.

doi:10.1042/0264-6021:3440643

Cited by 34 publications

(47 citation statements)

References 36 publications

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“…30 We now extend these findings to show that Bcl-x L is protective even when glycolysis is blocked by 2-DG. It is possible that 2-DG-6-phosphate produced by HK-mediated phosphorylation of 2-DG can enter the pentose phosphate shunt and allow NADPH recycling, 49 thereby maintaining a reduced cellular state and contributing towards cell survival.…”

Section: Discussionmentioning

confidence: 99%

Colony-stimulating factor-1 requires PI3-kinase-mediated metabolism for proliferation and survival in myeloid cells

Lee

States

2006

Cell Death Differ

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Colony-stimulating factor-1 (CSF-1) is essential for macrophage growth, differentiation and survival. Myeloid cells expressing a CSF-1 receptor mutant (DKI) show markedly impaired CSF-1-mediated proliferation and survival, accompanied by absent signal transducers and activators of transcription 3 (Stat3) phosphorylation and reduced PI3-kinase/Akt activity. Restoring phosphatidylinositol 3-kinase (PI3-kinase) but not Stat3 signals reverses the mitogenic defect. CSF-1-induced proliferation and survival are sensitive to glycolytic inhibitors, 2-deoxyglucose and 3-bromopyruvate. Consistent with a critical role for PI3-kinase-regulated glycolysis, DKI cells reconstituted with active PI3-kinase or Akt are hypersensitive to these inhibitors. CSF-1 upregulates hexokinase II (HKII) expression through PI3-kinase, and PI3-kinase transcriptionally activates the HKII promoter. Moreover, HKII overexpression partially restores mitogenicity. In contrast, Bcl-x L expression does not enhance long-term proliferation, although short-term cell death is suppressed in a glycolysis-independent manner. This study identifies robust PI3-kinase activation as essential for optimal CSF-1-mediated mitogenesis in myeloid cells, in part through regulation of HKII and support of glycolysis.

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Section: Discussionmentioning

confidence: 99%

Colony-stimulating factor-1 requires PI3-kinase-mediated metabolism for proliferation and survival in myeloid cells

Lee

States

2006

Cell Death Differ

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“…However, this needs to be directly verified using a catalytically inactive mutant of hexokinase. Other investigators have demonstrated that 2-deoxyglucose-6-phosphate, generated via the action of hexokinase, can be metabolized via the pentose phosphate pathway (PPP) in quantities sufficient to support redox coupling critical for cell survival (Le Goffe et al, 1999Goffe et al, , 2002 and redox coupling between this pathway and caspase-2 activation has also recently been described (Nutt et al, 2005), so potential metabolic contributions distal to glucose phosphorylation cannot be excluded (see below).…”

Section: Mitochondrial Hexokinases As Downstream Effectors Of Growth mentioning

confidence: 99%

“…The generation of glucose-6-phosphate is required for entry into the PPP (Figure 1). Thus, glucose phosphorylation by hexokinase could gate flux through this pathway and thereby directly contribute to both cellular redox status and resistance to oxidant-mediated cell death (Le Goffe et al, 1999Tian et al, 1999;Kurata et al, 2000). Glucose-6-phosphate dehydrogenase (G6PDH) activity is rate-limiting for PPP flux and is required for NADPH generation via this route.…”

Section: How Do Growth Factors and Akt Mediate Hexokinase-mitochondrimentioning

confidence: 99%

Mitochondrial hexokinases, novel mediators of the antiapoptotic effects of growth factors and Akt

2006

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Cell survival has been closely linked to both trophic growth factor signaling and cellular metabolism. Such couplings have obvious physiologic and pathophysiologic implications, but their underlying molecular bases remain incompletely defined. As a common mediator of both the metabolic and anti-apoptotic effects of growth factors, the serine/threonine kinase Akt -also known as protein kinase B or PKB -is capable of regulating and coordinating these inter-related processes. The glucose dependence of the antiapoptotic effects of growth factors and Akt plus a strong correlation between Akt-regulated mitochondrial hexokinase association and apoptotic susceptibility suggest a major role for hexokinases in these effects. Mitochondrial hexokinases catalyse the first obligatory step of glucose metabolism and directly couple extramitochondrial glycolysis to intramitochondrial oxidative phosphorylation, and are thus well suited to play this role. The ability of Akt to regulate energy metabolism appears to have evolutionarily preceded the capacity to control cell survival. This suggests that Akt-dependent metabolic regulatory functions may have given rise to glucose-dependent antiapoptotic effects that evolved as an adaptive sensing system involving hexokinases and serve to ensure mitochondrial homeostasis, thereby coupling metabolism to cell survival. We hypothesize that the enlistment of Akt and hexokinase in the control of mammalian cell apoptosis evolved as a response to the recruitment of mitochondria to the apoptotic cascade. The central importance of mitochondrial hexokinases in cell survival also suggests that they may represent viable therapeutic targets in cancer.

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“…The concentration of ni- trated proteins was estimated from the standard curve and expressed as micrograms of nitro-BSA equivalent per milligram of protein. 22 Cytochrome C Determination. Cytochrome c concentrations were determined on cytosolic fractions or on enriched mitochondrial fractions from livers of treated or untreated ob/ob mice.…”

Section: Methodsmentioning

confidence: 99%

Pivotal role of superoxide anion and beneficial effect of antioxidant molecules in murine steatohepatitis

et al. 2004

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Nonalcoholic fatty liver disease, frequently associated with obesity, can lead to nonalcoholic steatohepatitis (NASH) and cirrhosis. The pathophysiology of NASH is poorly understood, and no effective treatment is available. In view of a potential deleterious role for reactive oxygen species (ROS), we investigated the origin of ROS overproduction in NASH. Mitochondrial production of ROS and its alterations in the presence of antioxidant molecules were studied in livers from ob/ob mice that bear a mutation of the leptin gene and develop experimental NASH. N-acetyl-cysteine and the superoxide dismutase (SOD) mimics ambroxol, manganese [III] tetrakis (5,10,15,20 benzoic acid) (MnTBAP), and copper [II] diisopropyl salicylate (CuDIPS) were used to target different checkpoints of the oxidative cascade to determine the pathways involved in ROS production. Liver mitochondria from ob/ob mice generated more O 2°؊ than those of lean littermates (P < .01). Ex vivo, all three SOD mimics decreased O 2°؊ generation (P < .001) and totally inhibited lipid peroxidation (P < .001) versus untreated ob/ob mice. Those modifications were associated with in vivo improvements: MnTBAP and CuDIPS reduced weight (P < .02) and limited the extension of histological liver steatosis by 30% and 52%, respectively, versus untreated ob/ob mice. In conclusion, these data demonstrate deleterious effects of superoxide anions in NASH and point at the potential interest of nonpeptidyl mimics of SOD in the treatment of NASH in

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The in vitro manipulation of carbohydrate metabolism: a new strategy for deciphering the cellular defence mechanisms against nitric oxide attack

Cited by 34 publications

References 36 publications

Colony-stimulating factor-1 requires PI3-kinase-mediated metabolism for proliferation and survival in myeloid cells

Colony-stimulating factor-1 requires PI3-kinase-mediated metabolism for proliferation and survival in myeloid cells

Mitochondrial hexokinases, novel mediators of the antiapoptotic effects of growth factors and Akt

Pivotal role of superoxide anion and beneficial effect of antioxidant molecules in murine steatohepatitis

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