bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2020–09–27
six papers selected by
Sreeparna Banerjee, Middle East Technical University
  1. Glutamate is a non-invasive metabolic biomarker of IDH1 mutant glioma response to temozolomide treatment.
  2. Metabolic regulation of EGFR effector and feedback signaling in pancreatic cancer cells requires K-Ras.
  3. Quantitative Analysis of the Physiological Contributions of Glucose to the TCA Cycle.
  4. Rac1 and EGFR cooperate to activate Pak in response to nutrient stress.
  5. Rapid sensing of clinically relevant glutamine concentrations in human serum with metabolically engineered E. coli-based cell-free protein synthesis.
  6. Structural insight into HEMK2-TRMT112 mediated glutamine methylation.
  1. Cancer Res. 2020 Sep 21. pii: canres.1314.2020. [Epub ahead of print]
    Glutamate is a non-invasive metabolic biomarker of IDH1 mutant glioma response to temozolomide treatment.
    Elavarasan Subramani, Marina Radoul, Chloe Najac, Georgios Batsios, Abigail R Molloy, Donghyun Hong, Anne Marie Gillespie, Romelyn Delos Santos, Pavithra Viswanath, Joseph F Costello, Russell O Pieper, Sabrina M Ronen.
      Although lower-grade gliomas are driven by mutations in the isocitrate dehydrogenase 1 (IDH1) gene and are less aggressive than primary glioblastoma, they nonetheless generally recur. IDH1 mutant patients are increasingly being treated with temozolomide (TMZ), but early detection of response remains a challenge and there is a need for complementary imaging methods to assess response to therapy prior to tumor shrinkage. The goal of this study was to determine the value of magnetic resonance spectroscopy (MRS)-based metabolic changes for detection of response to TMZ in both genetically engineered and patient-derived mutant IDH1 models. Using 1H MRS in combination with chemometrics identified several metabolic alterations in TMZ-treated cells, including a significant increase in steady-state glutamate levels. This was confirmed in vivo, where the observed 1H MRS increase in glutamate/glutamine occurred prior to tumor shrinkage. Cells labeled with [1-13C]glucose and [3-13C]glutamine, the principal sources of cellular glutamate, showed that flux to glutamate both from glucose via the tricarboxylic acid cycle and from glutamine were increased following TMZ treatment. In line with these results, hyperpolarized [5-13C]glutamate produced from [2-13C]pyruvate and hyperpolarized [1-13C]glutamate produced from [1-13C]α-ketoglutarate were significantly higher in TMZ-treated cells compared to controls. Collectively, our findings identify 1H MRS-detectable elevation of glutamate and hyperpolarized 13C MRS-detectable glutamate production from either pyruvate or α-ketoglutarate as potential translatable metabolic biomarkers of response to TMZ treatment in mutant IDH1 glioma.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-1314
  2. Biochem Biophys Res Commun. 2020 Sep 21. pii: S0006-291X(20)31770-8. [Epub ahead of print]
    Metabolic regulation of EGFR effector and feedback signaling in pancreatic cancer cells requires K-Ras.
    Szu-Wei Lee, Cosimo Commisso.
      Nutrient stress driven by glutamine deficiency activates EGFR signaling in a subset of KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) cells. EGFR signaling in the context of glutamine starvation is thought to be instigated by the transcriptional upregulation of EGFR ligands and functions as an adaptation mechanism to allow PDAC cells to maintain metabolic fitness. Having a clear view of the intricate signaling cascades potentiated by the metabolic induction of EGFR is important in understanding how these effector pathways influence cancer progression. In this study, we examined the complex signaling that occurs in PDAC cells when EGFR is activated by glutamine deprivation. We elucidate that the metabolic activation of EGFR is principally mediated by HB-EGF, and that other members of the ErbB receptor tyrosine kinase family are not activated by glutamine starvation. Additionally, we determine that glutamine depletion-driven EGFR signaling is associated with a specific receptor phosphorylation known to participate in a feedback loop, a process that is dependent on Erk. Lastly, we determine that K-Ras is required for glutamine depletion-induced Erk activation, as well as EGFR feedback phosphorylation, but is dispensable for Akt activation. These data provide important insights into the regulation of EGFR signaling in the context of metabolic stresses.
    Keywords:  Akt; EGFR; Erk; Glutamine; Metabolism; Nutrient stress; Ras
    DOI:  https://doi.org/10.1016/j.bbrc.2020.09.029
  3. Cell Metab. 2020 Sep 16. pii: S1550-4131(20)30483-6. [Epub ahead of print]
    Quantitative Analysis of the Physiological Contributions of Glucose to the TCA Cycle.
    Shiyu Liu, Ziwei Dai, Daniel E Cooper, David G Kirsch, Jason W Locasale.
      The nutritional source for catabolism in the tricarboxylic acid (TCA) cycle is a fundamental question in metabolic physiology. Limited by data and mathematical analysis, controversy exists. Using isotope-labeling data in vivo across several experimental conditions, we construct multiple models of central carbon metabolism and develop methods based on metabolic flux analysis (MFA) to solve for the preferences of glucose, lactate, and other nutrients used in the TCA cycle. We show that in nearly all circumstances, glucose contributes more than lactate as a substrate to the TCA cycle. This conclusion is verified in different animal strains from different studies and different administrations of 13C glucose, and is extended to multiple tissue types. Thus, this quantitative analysis of organismal metabolism defines the relative contributions of nutrient fluxes in physiology, provides a resource for analysis of in vivo isotope tracing data, and concludes that glucose is the major nutrient used in mammals.
    Keywords:  TCA cycle; glucose metabolism; isotope tracing; lactate; liver metabolism; metabolic flux analysis; mitochondrial metabolism; multi-tissue modeling; parameter sensitivity analysis; quantitative biology; systems biology
    DOI:  https://doi.org/10.1016/j.cmet.2020.09.005
  4. Biochem Biophys Res Commun. 2020 Sep 21. pii: S0006-291X(20)31784-8. [Epub ahead of print]
    Rac1 and EGFR cooperate to activate Pak in response to nutrient stress.
    Szu-Wei Lee, Cosimo Commisso.
      The interplay between nutrient scarcity and signal transduction circuits is an important aspect of tumorigenesis that regulates many aspects of cancer progression. Glutamine is a critical nutrient for cancer cells, as it contributes to biosynthetic reactions that sustain cancer proliferation and growth. In tumors, because nutrient utilization can often outpace supply, glutamine levels can become limiting and oncogene-mediated metabolic rewiring triggers signaling cascades that support nutrient stress survival. Recently, we identified that in pancreatic ductal adenocarcinoma (PDAC) cells, glutamine depletion can trigger p21-activated kinase (Pak) activation through EGFR signaling as a means to circumvent metabolic stress. Here, we elucidate that glutamine starvation, as well EGF stimulation, can enhance the presence of many different Pak phosphoforms, and that this activation only occurs in a subset of PDAC cells. Pak is a well-established effector of Rac1, and while Rac1 mutant variants can modulate the metabolic induction of Pak phosphorylation, Rac1 inhibition only partially attenuates Pak activation upon glutamine depletion. We decipher that in order to efficiently suppress metabolic activation of Pak, both EGFR and Rac1 signaling must be inhibited. These results provide a mechanistic understanding of how glutamine-regulated signal transduction can control Pak activation in PDAC cells.
    Keywords:  EGFR; Glutamine; Nutrient stress; Pak; Pancreatic; Rac
    DOI:  https://doi.org/10.1016/j.bbrc.2020.09.043
  5. J Biotechnol. 2020 Sep 19. pii: S0168-1656(20)30247-9. [Epub ahead of print]
    Rapid sensing of clinically relevant glutamine concentrations in human serum with metabolically engineered E. coli-based cell-free protein synthesis.
    J Porter Hunt, R Jordan Barnett, Hannah Robinson, Mehran Soltani, J Andrew D Nelson, Bradley C Bundy.
      Bioavailable glutamine (Gln) is critical for metabolism, intestinal health, immune function, and cell signaling. Routine measurement of serum Gln concentrations could facilitate improved diagnosis and treatment of severe infections, anorexia nervosa, chronic kidney disease, diabetes, and cancer. Current methods for quantifying tissue Gln concentrations rely mainly on HPLC, which requires extensive sample preparation and expensive equipment. Consequently, patient Gln levels may be clinically underutilized. Cell-free protein synthesis (CFPS) is an emerging sensing platform with promising clinical applications, including detection of hormones, amino acids, nucleic acids, and other biomarkers. In this work, in vitro E. coli amino acid metabolism is engineered with methionine sulfoximine to inhibit glutamine synthetase and create a CFPS Gln sensor. The sensor features a strong signal-to-noise ratio and a detection range ideally suited to physiological Gln concentrations. Furthermore, it quantifies Gln concentration in the presence of human serum. This work demonstrates that CFPS reactions which harness the metabolic power of E. coli lysate may be engineered to detect clinically relevant analytes in human samples. This approach could lead to transformative point-of-care diagnostics and improved treatment regimens for a variety of diseases including cancer, diabetes, anorexia nervosa, chronic kidney disease, and severe infections.
    Keywords:  CFPS; cell-free protein synthesis; glutamine; metabolic engineering; methionine sulfoximine; serum
    DOI:  https://doi.org/10.1016/j.jbiotec.2020.09.011
  6. Biochem J. 2020 Sep 24. pii: BCJ20200594. [Epub ahead of print]
    Structural insight into HEMK2-TRMT112 mediated glutamine methylation.
    Jie Gao, Bin Wang, Huijuan Yu, Gao Wu, Cuihong Wang, Wenting Liu, Shanhui Liao, Liansheng Cheng, Zhongliang Zhu.
      Post-translational modifications (PTMs) play important roles in mediating protein functions in a wide variety of cellular events in vivo. HEMK2-TRMT112 heterodimer has been reported to be responsible for both histone lysine methylation and eukaryotic release factor 1 (eRF1) glutamine methylation. However, how HEMK2-TRMT112 complex recognizes and catalyzes eRF1 glutamine methylation is largely unknown. Here, we present two structures of HEMK2-TRMT112, with one bound to SAM and the other bound with SAH and methylglutamine (Qme). Structural analysis, complemented by mass spectrometry experiments, indicate that the HEMK2 utilizes a specific pocket to accommodate the substrate glutamine and catalyzes the subsequent methylation. Therefore, our work not only throws light on the protein glutamine methylation mechanism, but also reveals the dual activity of HEMK2 by catalyzing the methylation of both Lys and Gln.
    Keywords:  HEMK2; SAM/SAH; TRMT112; X-ray crystallography; glutamine methylation
    DOI:  https://doi.org/10.1042/BCJ20200594
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