Cancer Metabolism: Is Glutamine Sweeter Than Glucose?

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Cancer Metabolism: Is Glutamine Sweeter than Glucose?

Weiqin Lu,1 Helene Pelicano,1 and Peng Huang1,* 1Department of Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA *Correspondence: [email protected] DOI 10.1016/j.ccr.2010.08.017

Glutamine is an essential nutrient for cancer cells. In this issue of Cancer Cell, Wang et al. (2010) show that malignant transformation by Rho GTPases leads to activation of glutaminase, which converts glutamine to glutamate to fuel cancer cell metabolism. Inhibition of glutaminase by a small compound effectively suppresses oncogenic transformation.

It has been known for a long time that only provide carbon source. Glutamine is colony formation of cells with constitu- cancer cells have elevated aerobic glycol- another essential nutrient for cancer cells tively activated Rho GTPase and strongly ysis (the Warburg effect) and exhibit and is an abundant amino acid in the inhibited breast cancer cell proliferation in increased dependence on glutamine for serum. Essential functions of glutamine soft agar, confirming the important role of growth and proliferation. The active utiliza- include its conversion to glutamate as glutaminase in cancer cell metabolism. tion of glucose by cancer cells constitutes a metabolic intermediate to be channeled The authors further showed that gluta- the biochemical basis for 18fluoro-deoxy- into the TCA cycle and its function as minase activity was elevated in Dbl-trans- glucose-positron emission tomography a precursor for the biosynthesis of nucleic formed cells and that such increase in the (FDG-PET) used in clinical diagnosis of acids, certain amino acids, and gluta- enzyme activity was NF-kB dependent, cancer. Glutamine, although classified as thione (Figure 1). The mitochondrial likely through affecting the expression of a nonessential amino acid, is known for enzyme glutaminase (GLS) catalyzes the a yet unidentified molecule that might decades to be a key ingredient in the conversion of glutamine to glutamate. promote the phosphorylation of gluta- culture medium to support cancer cell Increased expression of glutaminase is minase. Interestingly, when cells were growth. However, the molecular mecha- often observed in tumor and rapidly supplied with a cell-permeable analog of nisms that link malignant transformation dividing cells. Interestingly, a recent study a-ketoglutarate, the inhibitory effect of and altered metabolism remain to be demonstrated that c-Myc enhanced GLS compound 968 was reversed, suggesting elucidated. Recent studies have revealed expression through suppression of miR- that the conversion of glutamine to gluta- some of the underlying mechanisms. For 23a/b (Gao et al., 2009), thus providing mate then to a-ketoglutarate for replen- instance, both HIF-1 and c-Myc have a molecular link between oncogenic ishment of the TCA cycle may be critical been shown to transcriptionally upregulate signal and glutamine metabolism. for cancer cell growth. multiple glycolytic enzymes, while the en- In this issue of Cancer Cell, Wang et al. The work by Wang et al. and the results hancement of pyruvate dehydrogenase (2010) report the identification of another from another study (Gao et al., 2009) kinase (PDK) by HIF-1 leads to inhibition class of oncogenic molecules, Rho suggest that different oncogenic signals of pyruvate entry into the tricarboxylic GTPases, which can promote glutamine (Rho GTPase and c-Myc) may cause acid cycle (TCA cycle) through phosphory- metabolism through upregulation of similar metabolic consequences through lation and inactivation of pyruvate de- glutaminase activity in a NF-kB-depen- activation of glutaminase, leading to an hydrogenase (Dang et al., 2008). AKT dent manner. Using a focus-formation increase in glutamine utilization by cancer activation is known to promote membrane assay to screen for compounds that might cells. Interestingly, two recent studies localization of glucose transporters suppress the transforming capacity of showed that the tumor suppressor p53 (GLUTs), activate phosphofructokinase-2 Rho GTPases activated by the oncogenic could transcriptionally activate the liver- (PFK2), and increase hexokinase II associ- molecule Dbl (Diffuse B cell lymphoma), type glutaminase (GLS2), promoting ation with mitochondria to facilitate the authors identified a tetrahydrobenzo glutamine metabolism and glutathione glycolysis (Robey and Hay, 2009). The [a] derivative (compound 968) capable of generation (Hu et al., 2010; Suzuki et al., tumor suppressor p53 exerts its effect on blocking Rho GTPase-induced transfor- 2010). The authors suggested that the energy metabolism by regulating PGM, mation in fibroblasts and inhibiting cancer increase in antioxidant capacity due to TIGAR, and SCO2 (Shaw, 2006). The cell growth. They then used a biotinylated elevated glutathione might contribute to increased dependency of cancer cells on compound in combination with streptavi- the tumor suppression function of p53. glycolysis has been considered as the din beads to pull down the molecules Since GLS and GLS2 have different Achilles’ heel that may be targeted for ther- that bind to the active moiety of com- enzyme kinetics and may be subjected apeutic purpose (Pelicano et al., 2006). pound 968 and identified the target to different regulatory mechanisms, the Although the glycolytic pathway gener- protein as the mitochondrial glutaminase roles of these two types of glutaminases ates ATP and produces metabolic inter- (kidney-type, or KGA). Specific knocking in cancer metabolism require further mediates for cancer cells, glucose can down of KGA by siRNA suppressed investigation. Nevertheless, the elevated

Cancer Cell 18, September 14, 2010 ª2010 Elsevier Inc. 199 Cancer Cell Previews

Glucose Glutamine bolic intervention strategies for different types of cancers. Targeting cancer meta- Myc ATP bolism seems to hold great promise for NF-κB cancer treatment and has been gaining Pyruvate miR-23a/b GLS Rho GTPase momentum in the recent years. It is important to identify the critical molecules that Other amino acids are preferentially used by cancer cells to Nucleotides Acetyl CoA Compound 968 maintain their altered metabolism but are not essential for the normal cells. The Asp OAA Glu tama te Citrate study by Wang et al. suggests that gluta- TCA minase seems to be a promising thera- Cycle ATP V α-KG peutic target. Preclinical and clinical GSH GABA studies are required to further test this Other amino acids possibility. NADH NAD+ REFERENCES Figure 1. Effect of Oncogenic Signals on Glutamine Metabolism through Regulation of Glutaminase Dang, C.V., Kim, J.W., Gao, P., and Yustein, J. The interconnection between glutamine metabolism and glucose metabolism is also shown. Inhibition of (2008). Nat. Rev. Cancer 8, 51–56. glutaminase by compound 968 suppresses oncogenic transformation induced by Rho GTPases. GLS, glutaminase; TCA cycle, tricarboxylic acid cycle; MRC, mitochondrial respiratory chain; V, mitochondrial DeBerardinis, R.J., Mancuso, A., Daikhin, E., Nis- respiratory complex V; OAA, oxaloacetate; Asp, aspartate; a-KG, a-ketoglutarate. sim, I., Yudkoff, M., Wehrli, S., and Thompson, C.B. (2007). Proc. Natl. Acad. Sci. USA 104, 19345–19350. glutamine catabolism appeared to play what impact of Rho-GTPase activation Gao, P., Tchernyshyov, I., Chang, T.C., Lee, Y.S., a major role in supporting malignant might have on glucose metabolism and Kita, K., Ochi, T., Zeller, K.I., De Marzo, A.M., Van Eyk, J.E., Mendell, J.T., and Dang, C.V. (2009). transformation, because suppression of determine the relative roles of these two Nature 458, 762–U100. glutaminase by the chemical inhibitor nutrients in fueling the transformed cells. 968 or siRNA strongly blocked the onco- To the cancer cells, is glutamine sweeter Hu, W., Zhang, C., Wu, R., Sun, Y., Levine, A., and Feng, Z. (2010). Proc. Natl. Acad. Sci. USA 107, gene-induced transformation. As such, than glucose? The answer to this question 7455–7460. the increased glutamine consumption by is likely cell context dependent. The meta- cancer cells should not be considered bolic proﬁles of different cancer cells may Pelicano, H., Martin, D.S., Xu, R.H., and Huang, P. (2006). Oncogene 25, 4633–4646. merely as a metabolic symptom or a by- likely be determined by their genotypes product of transformation. and the microenvironment they reside. Reitzer, L.J., Wice, B.M., and Kennell, D. (1979). J. Biol. Chem. 254, 2669–2676. Since glutamine can be metabolized to For instance, c-Myc may promote both produce ATP or function as a precursor glucose and glutamine utilization because Robey, R.B., and Hay, N. (2009). Semin. Cancer 19 for the synthesis of protein, nucleotides, of its ability to upregulate the glycolytic Biol. , 25–31. and lipid (DeBerardinis et al., 2007), it is enzymes and to activate GLS. In contrast, Shaw, R.J. (2006). Curr. Opin. Cell Biol. 18, important to determine if inhibition of certain papillomavirus-transformed cer- 598–608. glutaminase would lead to ATP decrease vical cancer cells (HeLa) may mainly use Suzuki, S., Tanaka, T., Poyurovsky, M.V., Nagano, or suppression of biomass synthesis. glutamine as the major energy source H., Mayama, T., Ohkubo, S., Lokshin, M., Hoso- Furthermore, because glucose, through (Reitzer et al., 1979). Thus, a detail under- kawa, H., Nakayama, T., Suzuki, Y., et al. (2010). Proc. Natl. Acad. Sci. USA 107, 7461–7466. glycolysis and the TCA cycle, can also standing of the complex effect of provide ATP and metabolic intermediates oncogenic signals and tissue microenvi- Wang, J.-B., Erickson, J.W., Fuji, R., Ramachan- dran, S., Gao, P., Dinavah, R., Wilson, K.F., Ambro- as the building blocks for cancer cells ronment on cancer cell metabolism is sio, A.L.B., Dias, S.M.G., Dang, C.V., and Cerione, (Figure 1), it would be interesting to test essential for the design of effective meta- R.A. (2010). Cancer Cell 18, this issue, 207–219.

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