bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2021–04–11
ten papers selected by
Sreeparna Banerjee, Middle East Technical University
  1. Cell-programmed nutrient partitioning in the tumour microenvironment.
  2. A Metabolic Reprogramming of Glycolysis and Glutamine Metabolism Is a Requisite for Renal Fibrogenesis-Why and How?
  3. A novel tumor suppressor CECR2 down regulation links glutamine metabolism contributes tumor growth in laryngeal squamous cell carcinoma.
  4. Mutant KRAS drives metabolic reprogramming and autophagic flux in premalignant pancreatic cells.
  5. Pancreatic β cells put the glutamine engine in reverse.
  6. Circ-MBOAT2 knockdown represses tumor progression and glutamine catabolism by miR-433-3p/GOT1 axis in pancreatic cancer.
  7. Endothelial cell autophagy in homeostasis and cancer.
  8. Immune-regulated IDO1-dependent tryptophan metabolism is source of one-carbon units for pancreatic cancer and stellate cells.
  9. Cell Metabolism and DNA Repair Pathways: Implications for Cancer Therapy.
  10. Posttranslational modification of pyruvate kinase type M2 (PKM2): novel regulation of its biological roles to be further discovered.
  1. Nature. 2021 Apr 07.
    Cell-programmed nutrient partitioning in the tumour microenvironment.
    Bradley I Reinfeld, Matthew Z Madden, Melissa M Wolf, Anna Chytil, Jackie E Bader, Andrew R Patterson, Ayaka Sugiura, Allison S Cohen, Ahmed Ali, Brian T Do, Alexander Muir, Caroline A Lewis, Rachel A Hongo, Kirsten L Young, Rachel E Brown, Vera M Todd, Tessa Huffstater, Abin Abraham, Richard T O'Neil, Matthew H Wilson, Fuxue Xin, M Noor Tantawy, W David Merryman, Rachelle W Johnson, Christopher S Williams, Emily F Mason, Frank M Mason, Katherine E Beckermann, Matthew G Vander Heiden, H Charles Manning, Jeffrey C Rathmell, W Kimryn Rathmell.
      Cancer cells characteristically consume glucose through Warburg metabolism1, a process that forms the basis of tumour imaging by positron emission tomography (PET). Tumour-infiltrating immune cells also rely on glucose, and impaired immune cell metabolism in the tumour microenvironment (TME) contributes to immune evasion by tumour cells2-4. However, whether the metabolism of immune cells is dysregulated in the TME by cell-intrinsic programs or by competition with cancer cells for limited nutrients remains unclear. Here we used PET tracers to measure the access to and uptake of glucose and glutamine by specific cell subsets in the TME. Notably, myeloid cells had the greatest capacity to take up intratumoral glucose, followed by T cells and cancer cells, across a range of cancer models. By contrast, cancer cells showed the highest uptake of glutamine. This distinct nutrient partitioning was programmed in a cell-intrinsic manner through mTORC1 signalling and the expression of genes related to the metabolism of glucose and glutamine. Inhibiting glutamine uptake enhanced glucose uptake across tumour-resident cell types, showing that glutamine metabolism suppresses glucose uptake without glucose being a limiting factor in the TME. Thus, cell-intrinsic programs drive the preferential acquisition of glucose and glutamine by immune and cancer cells, respectively. Cell-selective partitioning of these nutrients could be exploited to develop therapies and imaging strategies to enhance or monitor the metabolic programs and activities of specific cell populations in the TME.
    DOI:  https://doi.org/10.1038/s41586-021-03442-1
  2. Front Physiol. 2021 ;12 645857
    A Metabolic Reprogramming of Glycolysis and Glutamine Metabolism Is a Requisite for Renal Fibrogenesis-Why and How?
    Timothy D Hewitson, Edward R Smith.
      Chronic Kidney Disease (CKD) is characterized by organ remodeling and fibrosis due to failed wound repair after on-going or severe injury. Key to this process is the continued activation and presence of matrix-producing renal fibroblasts. In cancer, metabolic alterations help cells to acquire and maintain a malignant phenotype. More recent evidence suggests that something similar occurs in the fibroblast during activation. To support these functions, pro-fibrotic signals released in response to injury induce metabolic reprograming to meet the high bioenergetic and biosynthetic demands of the (myo)fibroblastic phenotype. Fibrogenic signals such as TGF-β1 trigger a rewiring of cellular metabolism with a shift toward glycolysis, uncoupling from mitochondrial oxidative phosphorylation, and enhanced glutamine metabolism. These adaptations may also have more widespread implications with redirection of acetyl-CoA directly linking changes in cellular metabolism and regulatory protein acetylation. Evidence also suggests that injury primes cells to these metabolic responses. In this review we discuss the key metabolic events that have led to a reappraisal of the regulation of fibroblast differentiation and function in CKD.
    Keywords:  TGF-β1; fibroblast; fibrosis; glutaminolysis; glycolysis; metabolic; metabolism; priming
    DOI:  https://doi.org/10.3389/fphys.2021.645857
  3. Clin Transl Oncol. 2021 Apr 07.
    A novel tumor suppressor CECR2 down regulation links glutamine metabolism contributes tumor growth in laryngeal squamous cell carcinoma.
    Xiaoting Wang, Chong Xu, Shengming Wang, Weijun Huang, Yuenan Liu, Xiaoxu Zhang, Niannian Li, Zhenfei Gao, Fan Wang, Nan Zhang, Jian Guan, Hongliang Yi, Feng Liu.
       PURPOSE: Glutamine plays an important role in tumor metabolism and progression. This research aimed to find out how Gln exert their effects on laryngeal squamous cell carcinoma (LSCC).
    METHODS: Cell proliferation was measured by CCK8 and EdU assay, mitochondrial bioenergetic activity was measured by mitochondrial stress tests. Gene expression profiling was revealed by RNA sequencing and validated by RT-qPCR. In LSCC patients, protein expression in tumor and adjacent tissues was examined and scored by IHC staining. RNAi was performed by stably expressed shRNA in TU177 cells. In vivo tumor growth analysis was performed using a nude mouse tumorigenicity model.
    RESULTS: Gln deprivation suppressed TU177 cell proliferation, which was restored by αKG supplementation. By transcriptomic analysis, we identified CECR2, which encodes a histone acetyl-lysine reader, as the downstream target gene for Gln and αKG. In LSCC patients, the expression of CECR2 in tumors was lower than adjacent tissues. Furthermore, deficiency of CECR2 promoted tumor cell growth both in vitro and in vivo, suggesting it has tumor suppressor effects. Besides, cell proliferation inhibited by Gln withdrawal could be restored by CECR2 depletion, and the proliferation boosted by αKG supplementation could be magnified either, suggested that CECR2 feedback suppressed Gln and αKG's effect on tumor growth. Transcriptomic profiling revealed CECR2 regulated the expression of a series of genes involved in tumor progression.
    CONCLUSION: We confirmed the Gln-αKG-CECR2 axis contributes to tumor growth in LSCC. This finding provided a potential therapeutic opportunity for the use of associated metabolites as a potential treatment for LSCC.
    Keywords:  CECR2; Glutamine metabolism; Laryngeal squamous cell carcinoma; α-ketoglutarate
    DOI:  https://doi.org/10.1007/s12094-021-02603-y
  4. Cancer Gene Ther. 2021 Apr 08.
    Mutant KRAS drives metabolic reprogramming and autophagic flux in premalignant pancreatic cells.
    Tatsunori Suzuki, Takahiro Kishikawa, Tatsuyuki Sato, Norihiko Takeda, Yuki Sugiura, Takahiro Seimiya, Kazuma Sekiba, Motoko Ohno, Takuma Iwata, Rei Ishibashi, Motoyuki Otsuka, Kazuhiko Koike.
      Mutational activation of the KRAS gene occurs in almost all pancreatic ductal adenocarcinoma (PDAC) and is the earliest molecular event in their carcinogenesis. Evidence has accumulated of the metabolic reprogramming in PDAC, such as amino acid homeostasis and autophagic flux. However, the biological effects of KRAS mutation on metabolic reprogramming at the earlier stages of PDAC carcinogenesis are unclear. Here we report dynamic metabolic reprogramming in immortalized human non-cancerous pancreatic ductal epithelial cells, in which a KRAS mutation was induced by gene-editing, which may mimic early pancreatic carcinogenesis. Similar to the cases of PDAC, KRAS gene mutation increased the dependency on glucose and glutamine for maintaining the intracellular redox balance. In addition, the intracellular levels of amino acids were significantly decreased because of active protein synthesis, and the cells required greater autophagic flux to maintain their viability. The lysosomal inhibitor chloroquine significantly inhibited cell proliferation. Therefore, metabolic reprogramming is an early event in carcinogenesis initiated by KRAS gene mutation, suggesting a rationale for the development of nutritional interventions that suppress or delay the development of PDAC.
    DOI:  https://doi.org/10.1038/s41417-021-00326-4
  5. Cell Metab. 2021 Apr 06. pii: S1550-4131(21)00117-0. [Epub ahead of print]33(4): 702-704
    Pancreatic β cells put the glutamine engine in reverse.
    Evan C Lien, Matthew G Vander Heiden.
      The metabolism of nutrients other than glucose influences insulin secretion by pancreatic β cells, but the mechanisms involved are incompletely understood. In this issue of Cell Metabolism, Zhang et al. (2020) report that reductive glutamine metabolism generates cytosolic NADPH to promote insulin secretion by β cells.
    DOI:  https://doi.org/10.1016/j.cmet.2021.03.010
  6. J Exp Clin Cancer Res. 2021 Apr 08. 40(1): 124
    Circ-MBOAT2 knockdown represses tumor progression and glutamine catabolism by miR-433-3p/GOT1 axis in pancreatic cancer.
    Xiaoxiao Zhou, Kun Liu, Jing Cui, Jiongxin Xiong, Heshui Wu, Tao Peng, Yao Guo.
       BACKGROUND: Pancreatic cancer is a malignant tumor and ranks the sixth in incidence among cancers. Circular RNA (circRNA) has been reported to regulate the progression of pancreatic cancer. However, the effects of circ-membrane bound O-acyltransferase domain containing 2 (circ-MBOAT2) on regulating pancreatic cancer process were unclear.
    METHODS: The expression levels of circ-MBOAT2, microRNA-433-3p (miR-433-3p) and glutamic-oxaloacetic transaminase 1 (GOT1) mRNA were detected by quantitative real-time polymerase chain reaction (qRT-PCR). GOT1 protein expression was determined by western blot analysis. Cell proliferation was illustrated by 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) and cell colony formation assay. Cell apoptosis was demonstrated by flow cytometry analysis. Cell invasion and migration were investigated by transwell invasion and wound-healing assays. Glutamine catabolism was explained by detecting glutamine consumption, alpha ketoglutarate (α-KG) production and glutamate production. In vivo assay was performed to illustrate the impacts of circ-MBOAT2 silencing on tumor formation in vivo. The binding relationship between miR-433-3p and circ-MBOAT2 or GOT1 was predicted by circinteractome or starbase online databases, and identified by dual-luciferase reporter assay.
    RESULTS: Circ-MBOAT2 and GOT1 expression were significantly upregulated, while miR-433-3p expression was downregulated in pancreatic cancer tissues and cells compared with normal pancreatic tissues or cells. Circ-MBOAT2 silencing repressed cell proliferation, migration, invasion and glutamine catabolism, whereas promoted cell apoptosis in pancreatic cancer. Additionally, circ-MBOAT2 acted as a sponge of miR-433-3p, which was found to be associate with GOT1. MiR-433-3p inhibitors hindered circ-MBOAT2 silencing-mediated impacts on pancreatic cancer progression and glutamine catabolism. Furthermore, circ-MBOAT2 silencing repressed tumor formation in vivo.
    CONCLUSION: Circ-MBOAT2 modulated tumor development and glutamine catabolism by miR-433-3p/GOT1 axis in pancreatic cancer. This finding suggests that circ-MBOAT2 may be a therapeutic target for pancreatic cancer.
    Keywords:  Circ-MBOAT2; GOT1; Pancreatic cancer; miR-433-3p
    DOI:  https://doi.org/10.1186/s13046-021-01894-x
  7. FEBS Lett. 2021 Apr 09.
    Endothelial cell autophagy in homeostasis and cancer.
    Jelle Verhoeven, Jef Baelen, Madhur Agrawal, Patrizia Agostinis.
      Autophagy, the major lysosomal pathway for the degradation and recycling of cytoplasmic materials, is increasingly recognized as a major player in endothelial cell (EC) biology and vascular pathology. Particularly in solid tumors, tumor microenvironmental stress such as hypoxia, nutrient deprivation, inflammatory mediators and metabolic aberrations stimulate autophagy in tumor-associated blood vessels. Increased autophagy in ECs may serve as a mechanism to alleviate stress and restrict exacerbated inflammatory responses. However, increased autophagy in tumor-associated ECs can re-model metabolic pathways and affect the trafficking and surface availability of key mediators and regulators of the interplay between EC and immune cells. In line with this, heightened EC autophagy is involved in pathological angiogenesis, inflammatory and immune responses. Here we review major cellular and molecular mechanisms regulated by autophagy in ECs under physiological conditions and discuss recent evidence implicating EC autophagy in tumor angiogenesis and immunosurveillance.
    Keywords:  Autophagy; Cancer; Endothelial cells; Immunosurveillance; Tumor vasculature
    DOI:  https://doi.org/10.1002/1873-3468.14087
  8. Mol Cell. 2021 Apr 04. pii: S1097-2765(21)00214-8. [Epub ahead of print]
    Immune-regulated IDO1-dependent tryptophan metabolism is source of one-carbon units for pancreatic cancer and stellate cells.
    Alice Clare Newman, Mattia Falcone, Alejandro Huerta Uribe, Tong Zhang, Dimitris Athineos, Matthias Pietzke, Alexei Vazquez, Karen Blyth, Oliver David Kenneth Maddocks.
      Cancer cells adapt their metabolism to support elevated energetic and anabolic demands of proliferation. Folate-dependent one-carbon metabolism is a critical metabolic process underpinning cellular proliferation supplying carbons for the synthesis of nucleotides incorporated into DNA and RNA. Recent research has focused on the nutrients that supply one-carbons to the folate cycle, particularly serine. Tryptophan is a theoretical source of one-carbon units through metabolism by IDO1, an enzyme intensively investigated in the context of tumor immune evasion. Using in vitro and in vivo pancreatic cancer models, we show that IDO1 expression is highly context dependent, influenced by attachment-independent growth and the canonical activator IFNγ. In IDO1-expressing cancer cells, tryptophan is a bona fide one-carbon donor for purine nucleotide synthesis in vitro and in vivo. Furthermore, we show that cancer cells release tryptophan-derived formate, which can be used by pancreatic stellate cells to support purine nucleotide synthesis.
    Keywords:  IDO1; IFNγ; PDAC; cancer immunology; cancer metabolism; epacadostat; formate; immunometabolism; immunotherapy; one-carbon metabolism; pancreas; serine; stellate cells; tryptophan; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.molcel.2021.03.019
  9. Front Cell Dev Biol. 2021 ;9 633305
    Cell Metabolism and DNA Repair Pathways: Implications for Cancer Therapy.
    Thais Sobanski, Maddison Rose, Amila Suraweera, Kenneth O'Byrne, Derek J Richard, Emma Bolderson.
      DNA repair and metabolic pathways are vital to maintain cellular homeostasis in normal human cells. Both of these pathways, however, undergo extensive changes during tumorigenesis, including modifications that promote rapid growth, genetic heterogeneity, and survival. While these two areas of research have remained relatively distinct, there is growing evidence that the pathways are interdependent and intrinsically linked. Therapeutic interventions that target metabolism or DNA repair systems have entered clinical practice in recent years, highlighting the potential of targeting these pathways in cancer. Further exploration of the links between metabolic and DNA repair pathways may open new therapeutic avenues in the future. Here, we discuss the dependence of DNA repair processes upon cellular metabolism; including the production of nucleotides required for repair, the necessity of metabolic pathways for the chromatin remodeling required for DNA repair, and the ways in which metabolism itself can induce and prevent DNA damage. We will also discuss the roles of metabolic proteins in DNA repair and, conversely, how DNA repair proteins can impact upon cell metabolism. Finally, we will discuss how further research may open therapeutic avenues in the treatment of cancer.
    Keywords:  DNA repair; cell metabolism; glycolysis; homologous recombination; non-homologous end-joining; tumor metabolic reprogramming; warburg effect
    DOI:  https://doi.org/10.3389/fcell.2021.633305
  10. J Physiol Biochem. 2021 Apr 09.
    Posttranslational modification of pyruvate kinase type M2 (PKM2): novel regulation of its biological roles to be further discovered.
    Shutao Zheng, Qing Liu, Tao Liu, Xiaomei Lu.
      PKM2, pyruvate kinase type M2, has been shown to play a key role in aerobic glycolysis and to regulate the malignant behaviors of cancer cells. Recently, PKM2 has been revealed to hold dual metabolic and nonmetabolic roles. Working as both a pyruvate kinase with catalytic activity and a protein kinase that phosphorylates its substrates, PKM2 stands at the crossroads of glycolysis and tumor growth. Recently, it was revealed that the catalytic activity of PKM2 can be regulated by its posttranslational modification (PTM). Several PTM types, including phosphorylation, methylation, acetylation, oxidation, hydroxylation, succinylation, and glycylation, have been gradually identified on different amino acid residues of the PKM2 coding sequence. In this review, we highlight the recent advancements in understanding PKM2 PTMs and the regulatory roles conferred by PTMs during anaerobic glycolysis in tumors.
    Keywords:  Acetylation; Anaerobic glycolysis; Methylation; PKM2; Phosphorylation; Posttranslational modification (PTM); Warburg effect
    DOI:  https://doi.org/10.1007/s13105-021-00813-0
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