CELL PROLIFERATION, THE WARBURG EFFECT, AND GLUTAMINE METABOLISM

The central role of glutamine in cellular proliferation was established in the 1950s by Harry Eagle, who showed that glutamine is required at concentrations above all other amino acids to sustain the growth and proliferation of cultured cells (Eagle et al. 1956); indeed, every scientist who does cell culture knows that growth medium must be supplemented with glutamine at supraphysiological concentrations of 2-4 mM in order to support optimal growth conditions. In vivo, the physiological role of glutamine in driving cell growth and regeneration is reflected by its consumption and use as a primary metabolic fuel in proliferative tissues such as activated immune cells and gut epithelia (Windmueller and Spaeth 1978; Newsholme 2001; Macintyre and Rathmell 2013).

Cell proliferation likewise obviously plays a central role in tumorigenesis; thus, alteration of glutamine metabolism in cancer has garnered progressively increased attention over the last decade. These contemporary efforts reprise of some of the seminal works performed in the twentieth century but are now guided and informed by data from the human genome project and technological advances in molecular biology, imaging, proteomics, and metabolomics. A search of PubMed confirms this perception: the number of articles published on “glutamine metabolism” and cancer from 2004 to 2008 was 18. The subsequent 5-year period from 2009 to 2013 yielded 88 published articles. In 2014 alone, 39 articles on this topic were published, and in 10 months into 2015, 44 articles have appeared on this topic. The graph shown in Figure 19.3 displays this trend. Increased interest in glutamine metabolism parallels the resurrected interest of the cancer research community in targeting metabolic alterations in carcinogenesis as potential therapies (Jang et al. 2013). Leading this vanguard was the rediscovery of the “Warburg effect”—enhanced rates of glycolytic metabolism even in the face of normal oxygen tensions, named after Otto Warburg, the Nobel

Growing research interest in cancer glutamine metabolism

FIGURE 19.3 Growing research interest in cancer glutamine metabolism. The number of publications focusing on glutamine metabolism in cancer as indexed by PubMed. Note the annual increase in publications since 2010. The first 10 years of the twenty-first century yielded 34 publications; the ensuing five years (2010-2014) yielded 118, with 65 in 2015. The entire twentieth century produced 64 papers on this topic (within the limits of search error), many of which laid the foundation for current research in this resurrected field.

Prize-winning biochemist who first made this observation in cancerous versus normal tissues (Hsu and Sabatini 2008). Both glucose and glutamine metabolism are altered and enhanced as part of the Warburg effect (Vander Heiden et al. 2009) through familiar oncogenic signaling pathways such as Myc and E2F/Rb (Dang 2012; Reynolds et al. 2014) that increase glutaminase and glutamine transporter expression (Dang 2010). Indeed, the core principles and mechanisms that are deployed to achieve rapid cellular proliferation in normal physiological functions such as lymphocyte activation (Macintyre and Rathmell 2013) appear to be coopted and sustained in cancer (Diaz-Ruiz et al. 2011; Agathocleous and Harris 2013).

Glutamine has widely been considered to be predominantly metabolized as a primary oxidative fuel for ATP generation via the TCA cycle such as in enterocytes as shown by the seminal work of Herbert Windmueller (Windmueller and Spaeth 1978) and in activated immune cells (Le et al. 2012). However, a long hypothesized and recently demonstrated role for glutamine in lipid biosynthesis has gained recognition, and is prominent particularly under conditions of hypoxia or the Warburg effect. This pathway involves the reductive carboxylation of glutamine-derived 2-oxoglu- tarate (a-ketoglutarate) by IDH1 (Metallo et al. 2012). A PubMed search reveals that this pathway was first described in cancer cells in 1995, (Holleran et al. 1995) and then for over a decade nothing more was published. From 2007 to 2015, a flourish of 23 papers were published on this pathway from a number of groups, demonstrating that a substantial disposition of glutamine-derived carbons into lipids occurs in cancer cells via the reductive carboxylation of 2-oxoglutarate by IDH1, essentially reversing the first two steps of the TCA cycle, reforming citrate, which is subsequently converted to oxaloacetate and acetyl-CoA by ATP citrate lyase. While the reductive carboxylation of glutamine-derived 2-oxoglutarate provides building blocks (acetyl-CoA and NADPH) for membrane biosynthesis, mutations in IDH1 likewise lead to the production of 2-hydroxyglutarate, a novel metabolite that exerts several oncogenic effects on cells (Yen et al. 2010). The mutations in IDH1 are druggable, and might offer therapeutic opportunities for cancer (Li et al. 2015). IDH1/2 thus serves as a nexus for glutamine-related metabolic therapy in cancer.

 
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