Glutamine Connections

RESEARCH HIGHLIGHTS Nature Reviews Cancer | AOP, published online 12 April 2013; doi:10.1038/nrc3515 METABOLISM because an orthologue of this protein, Tap42, is known to have this function in yeast. Indeed, expression of α4 Glutamine connections protected mouse embryo fibroblasts (MEFs) and human fibrosarcoma As a result of the Warburg effect glutamine metabolism by showing cells from the cytotoxic effects of (aerobic glycolysis) in cancer cells, that VHL deficiency sensitizes RCC glutamine deprivation. Using various fewer glucose-derived metabolites cells and xenografts to inhibitors of genetic, biochemical and proteomic feed into the Krebs cycle. Thus, can- glutaminase, the enzyme that catalyses approaches, the authors showed that cer cells typically have an increased the first step of glutamine metabolism. glutamine deprivation triggers an reliance on alternative metabolites In a separate study, Son et al. increase in ROS levels, which leads to replenish Krebs cycle inter- analysed the contribution of activated to the α4-mediated assembly of a mediates, and the amino acid KRAS to metabolism in pancreatic B55α-subunit-containing protein glutamine is one such metabolite. ductal adenocarcinoma (PDAC) cells phosphatase 2A (PP2A) complex. This Three new studies have character- that are dependent on glutamine. results in the activation of p53 and the ized molecular links between Using genetic and pharmacological induction of pro-survival p53 target glutamine metabolism and key interventions the authors found that genes, such as Cdkn1a (which encodes cancer signalling pathways. the growth of KRAS-mutant PDAC p21) and Gadd45a. Consistent with Hyperactivation of the transcrip- cells and tumour xenografts does not this, the growth of fibrosarcoma tion factors hypoxia-inducible fac- rely on glutamate dehydrogenase 1 xenograft tumours (the cores of Lara Crow/NPG Lara tor 1α (HIF1α) and HIF2α through (GLUD1; also known as GDH1) which were shown to have low levels loss-of-function mutations in the in the conversion of glutamine of glutamine) was inhibited by B55α von Hippel–Lindau (VHL) tumour to α-ketoglutarate for use in the knockdown, and p53-deficient suppressor gene commonly occurs Krebs cycle, and instead requires a HCT116 cells in vitro were more sen- in renal cell carcinoma (RCC). The non-canonical route involving the sitive to glutamine deprivation than authors of the first new study had GOT1 aspartate transaminase to p53-wild-type controls. Reid et al. previously shown that VHL-mutant convert glutamine-derived aspartate concluded that glutamine is required RCC cell lines use glutamine to to oxaloacetate, which can be used to generate reduced glutathione, again generate citrate and lipids through the to generate malate and pyruvate. to maintain the cellular redox state. reductive carboxylation of glutamine- This series of reactions increases Blocking metabolic functions as a derived α-ketoglutarate, and that HIF NADPH levels and helps to maintain therapeutic approach raises the chal- activity in hypoxic cells promotes the the cellular redox state through the lenge of avoiding toxicity in normal conversion of glucose to lactate, thus generation of reduced glutathione. tissues. However, these molecular preventing the use of glucose in the Indeed, glutamine deprivation links between cancer signalling Krebs cycle. To determine whether results in increased reactive oxygen pathways and altered glutamine these findings are linked in RCCs with species (ROS) levels in PDAC cells, metabolism support the applicability mutant VHL, Gameiro et al. carried and inhibitors of glutaminase syner- of anticancer therapeutic approaches out manipulations in RCC cells — gized with H2O2 to kill PDAC cells. that are based on glutamine depriva- such as by expressing mutant VHL or Knockdown of KRAS resulted in tion and suggest that their efficacy VHL-insensitive HIF subunits — and GOT1 downregulation and reduced might be enhanced in p53-deficient used metabolic profiling in vitro and metabolic flux through this non- tumours or in combination with in tumour-bearing mice to show that canonical route, thus demonstrating other ROS-generating stresses. loss of HIF regulation by VHL is suf- the role of mutant KRAS in specifying Darren J. Burgess ficient to switch the Krebs cycle inputs the use of this pathway. ORIGINAL RESEARCH PAPERS Gameiro, P. A. from mostly glucose-derived inputs As glutamine deprivation can et al. In vivo HIF-mediated reductive carboxylation glutamine to mostly glutamine-derived inputs. occur naturally through the increased is regulated by citrate levels and sensitizes VHL- is required They also found that replenishing use of glutamine reserves by tumours, deficient cells to glutamine deprivation. Cell Metab. 17, 372–385 (2013) | Son, J. et al. Glutamine to generate citrate levels could block the switch and is a goal of various therapeutic supports pancreatic cancer growth through a to glutamine usage, thus intracellular approaches, it is important to under- KRAS-regulated metabolic pathway. Nature 27 reduced Mar 2013 (doi:10.1038/nature12040) | Reid, M. A. citrate deficiency might promote the stand how cells respond to glutamine et al. The B55α subunit of PP2A drives a p53- glutathione switch to glutamine use. Finally, deprivation. Reid et al. tested whether dependent metabolic adaptation to glutamine the authors highlighted the thera- α4 (also known as IGBP1) has a role in deprivation. Mol. Cell 13 Mar 2013 (doi:10.1016/j. molcel.2013.02.008) peutic relevance of this reliance on the response to glutamine deprivation, NATURE REVIEWS | CANCER VOLUME 13 | MAY 2013 © 2013 Macmillan Publishers Limited. All rights reserved.

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