The hexosamine biosynthetic pathway couples growth factor-induced glutamine uptake to glucose metabolism. Genes Dev

Department of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Genes & development (Impact Factor: 10.8). 12/2010; 24(24):2784-99. DOI: 10.1101/gad.1985910
Source: PubMed

ABSTRACT Glucose and glutamine serve as the two primary carbon sources in proliferating cells, and uptake of both nutrients is directed by growth factor signaling. Although either glucose or glutamine can potentially support mitochondrial tricarboxylic acid (TCA) cycle integrity and ATP production, we found that glucose deprivation led to a marked reduction in glutamine uptake and progressive cellular atrophy in multiple mammalian cell types. Despite the continuous presence of growth factor and an abundant supply of extracellular glutamine, interleukin-3 (IL-3)-dependent cells were unable to maintain TCA cycle metabolite pools or receptor-dependent signal transduction when deprived of glucose. This was due at least in part to down-regulation of IL-3 receptor α (IL-3Rα) surface expression in the absence of glucose. Treatment of glucose-starved cells with N-acetylglucosamine (GlcNAc) to maintain hexosamine biosynthesis restored mitochondrial metabolism and cell growth by promoting IL-3-dependent glutamine uptake and metabolism. Thus, glucose metabolism through the hexosamine biosynthetic pathway is required to sustain sufficient growth factor signaling and glutamine uptake to support cell growth and survival.

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Available from: Hilary Coller, Sep 29, 2015
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    • "Glycine decarboxylase (GLDC), an enzyme upregulated in several cancers, can drive the flux from serine to pyrimidine synthesis [41], but recent evidence indicates that serine, not glycine, supports cancer cell proliferation [42]. Similarly, the PPP and the hexosamine biosynthesis pathway (HBP) use glucose for anabolism and protein glycosylation (see below) [40,43-46]. "
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    09/2014; 2(1):19. DOI:10.1186/2049-3002-2-19
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    • "The ability of AMPK to phosphorylate OGT illustrates one way in which the LKB1-AMPK and the HBP-OGT pathways intersect. These two signaling pathways integrate information about nutrient availability (high nutrients versus low nutrients) and have opposite biological functions (40,41). The LKB1-AMPK pathway in general inhibits cell growth through downstream targets such as TSC2 and ACC1 (31,36,38), whereas the HBP-OGT pathway regulates gene transcription to promote cell growth. "
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    • "This led us to ask whether exogenous supplementation of HP intermediates could alter TM toxicity. Indeed, WT animals successfully developed on TM plates with added GlcNAc or UDP-GlcNAc (Figures 1H and 1I), suggesting that dietary GlcNAc is utilized in the HP, as shown previously in cultured cells (Wellen et al., 2010). Additional data showed that GFAT-1 gof rendered animals resistant to TM-induced inhibition of N-glycosylation and subsequent UPR stress signaling (Figures S1I and S1P). "
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