bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2023‒06‒11
eleven papers selected by
Sreeparna Banerjee
Middle East Technical University

  1. Front Oncol. 2023 ;13 1186539
      Arginine, glutamine, and the branched chain amino acids (BCAAs) are a focus of increased interest in the field of oncology due to their importance in the metabolic reprogramming of cancer cells. In the tumor microenvironment (TME), these amino acids serve to support the elevated biosynthetic and energy demands of cancer cells, while simultaneously maintaining the growth, homeostasis, and effector function of tumor-infiltrating immune cells. To escape immune destruction, cancer cells utilize a variety of mechanisms to suppress the cytotoxic activity of effector T cells, facilitating T cell exhaustion. One such mechanism is the ability of cancer cells to overexpress metabolic enzymes specializing in the catabolism of arginine, glutamine, and the BCAAs in the TME. The action of such enzymes supplies cancer cells with metabolic intermediates that feed into the TCA cycle, supporting energy generation, or providing precursors for purine, pyrimidine, and polyamine biosynthesis. Armed with substantial metabolic flexibility, cancer cells redirect amino acids from the TME for their own advantage and growth, while leaving the local infiltrating effector T cells deprived of essential nutrients. This review addresses the metabolic pressure that cancer cells exert over immune cells in the TME by up-regulating amino acid metabolism, while discussing opportunities for targeting amino acid metabolism for therapeutic intervention. Special emphasis is given to the crosstalk between arginine, glutamine, and BCAA metabolism in affording cancer cells with metabolic dominance in the TME.
    Keywords:  TME; arginine; glutamine; isoleucine; leucine; metabolism; valine
  2. Curr Osteoporos Rep. 2023 Jun 06.
      PURPOSE OF REVIEW: Breast and prostate tumors frequently metastasize to the bone, but the underlying mechanisms for osteotropism remain elusive. An emerging feature of metastatic progression is metabolic adaptation of cancer cells to new environments. This review will summarize the recent advances on how cancer cells utilize amino acid metabolism during metastasis, from early dissemination to interactions with the bone microenvironment.RECENT FINDINGS: Recent studies have suggested that certain metabolic preferences for amino acids may be associated with bone metastasis. Once in the bone microenvironment, cancer cells encounter a favorable microenvironment, where a changing nutrient composition of the tumor-bone microenvironment may alter metabolic interactions with bone-resident cells to further drive metastatic outgrowth. Enhanced amino acid metabolic programs are associated with bone metastatic disease and may be further augmented by the bone microenvironment. Additional studies are necessary to fully elucidate the role of amino acid metabolism on bone metastasis.
    Keywords:  Amino acids; Bone; Cancer; Metabolism; Metastasis; Microenvironment
  3. Eur J Pharmacol. 2023 Jun 03. pii: S0014-2999(23)00341-2. [Epub ahead of print] 175830
      Amino acid requirement of metabolically active cells is a key element in cellular survival. Of note, cancer cells were shown to have an abnormal metabolism and high-energy requirements including the high amino acid requirement needed for growth factor synthesis. Thus, amino acid deprivation is considered a novel approach to inhibit cancer cell proliferation and offer potential treatment prospects. Accordingly, arginine was proven to play a significant role in cancer cell metabolism and therapy. Arginine depletion induced cell death in various types of cancer cells. Also, the various mechanisms of arginine deprivation, e.g., apoptosis and autophagy were summarized. Finally, the adaptive mechanisms of arginine were also investigated. Several malignant tumors had high amino acid metabolic requirements to accommodate their rapid growth. Antimetabolites that prevent the production of amino acids were also developed as anticancer therapies and are currently under clinical investigation. The aim of this review is to provide a concise literature on arginine metabolism and deprivation, its effects in different tumors, its different modes of action, as well as the related cancerous escape mechanisms.
    Keywords:  Apoptosis; Arginine depraving factors; Arginine deprivation; Autophagy; Cancer therapy; Escape mechanisms
  4. J Hematol Oncol. 2023 Jun 05. 16(1): 59
      Amino acids are basic nutrients for immune cells during organ development, tissue homeostasis, and the immune response. Regarding metabolic reprogramming in the tumor microenvironment, dysregulation of amino acid consumption in immune cells is an important underlying mechanism leading to impaired anti-tumor immunity. Emerging studies have revealed that altered amino acid metabolism is tightly linked to tumor outgrowth, metastasis, and therapeutic resistance through governing the fate of various immune cells. During these processes, the concentration of free amino acids, their membrane bound transporters, key metabolic enzymes, and sensors such as mTOR and GCN2 play critical roles in controlling immune cell differentiation and function. As such, anti-cancer immune responses could be enhanced by supplement of specific essential amino acids, or targeting the metabolic enzymes or their sensors, thereby developing novel adjuvant immune therapeutic modalities. To further dissect metabolic regulation of anti-tumor immunity, this review summarizes the regulatory mechanisms governing reprogramming of amino acid metabolism and their effects on the phenotypes and functions of tumor-infiltrating immune cells to propose novel approaches that could be exploited to rewire amino acid metabolism and enhance cancer immunotherapy.
    Keywords:  Amino acids; Immune cells; SLC transporters; Tumor microenvironment; mTOR
  5. J Ovarian Res. 2023 Jun 05. 16(1): 108
      The mortality rate of epithelial ovarian cancer (EOC) remains the first in malignant tumors of the female reproductive system. The characteristics of rapid proliferation, extensive implanted metastasis, and treatment resistance of cancer cells require an extensive metabolism rewiring during the progression of cancer development. EOC cells satisfy their rapid proliferation through the rewiring of perception, uptake, utilization, and regulation of glucose, lipids, and amino acids. Further, complete implanted metastasis by acquiring a superior advantage in microenvironment nutrients competing. Lastly, success evolves under the treatment stress of chemotherapy and targets therapy. Understanding the above metabolic characteristics of EOCs helps to find new methods of its treatment.
  6. Methods Mol Biol. 2023 ;2676 147-156
      Gln methylation is a newly identified histone mark and mediates ribosomal biogenesis. Site-specifically Gln-methylated proteins are valuable tools to elucidate the biological implications of this modification. Herein, we describe a protocol to generate histones with site-specific Gln methylation in a semisynthetic manner. Firstly, an esterified glutamic acid analogue (BnE) is genetically encoded into proteins by genetic code expansion with high efficiency, which can be quantitatively converted into an acyl hydrazide via hydrazinolysis. Then, through a reaction with acetyl acetone, the acyl hydrazide is converted to reactive Knorr pyrazole. Finally, the in situ generated Knorr pyrazole is incubated with methylamine to give Gln methylation.
    Keywords:  Acyl hydrazide; Genetic code expansion; Glutamic acid analogue; Histone Gln methylation; Knorr pyrazole
  7. Front Oncol. 2023 ;13 1108729
      T-cell lymphoma is a hematologic neoplasm derived from the lymphoid lineage. It belongs to a diverse group of malignant disorders, mostly affecting the young population worldwide, that vary with respect to molecular features as well as genetic and clinical complexities. Cancer cells rewire the cellular metabolism, persuading it to meet new demands of growth and proliferation. Furthermore, the metabolic alterations and heterogeneity are aberrantly driven in cancer by a combination of genetic and non-genetic factors, including the tumor microenvironment. New insight into cancer metabolism highlights the importance of nutrient supply to tumor development and therapeutic responses. Importantly, oxidative stress due to an imbalance in the redox status of reactive species via exogenous and/or endogenous factors is closely related to multiple aspects of cancer. This alters the signaling pathways governed through the multiple intracellular signal transduction and transcription factors, leading to tumor progression. These oncogenic signaling molecules are regulated through different redox sensors, including nuclear factor-erythroid 2 related factor 2 (Nrf2), phase-II antioxidant enzyme, and NQO1 (NADPH quinone oxidoreductase (1). The existing understanding of the molecular mechanisms of T-cell lymphoma regulation through the cross-talk of redox sensors under the influence of metabolic vulnerability is not well explored. This review highlights the role of the redox dynamics, orchestra of signaling, and genetic regulation involved in T-cell lymphoma progression in addition to the challenges to their etiology, treatment, and clinical response in light of recent updates.
    Keywords:  NF-κB; Nrf2; T-cell lymphoma; cancer metabolism; redox status; signaling pathways
  8. Annu Rev Nutr. 2023 Jun 07.
      Amino acids derived from protein digestion are important nutrients for the growth and maintenance of organisms. Approximately half of the 20 proteinogenic amino acids can be synthesized by mammalian organisms, while the other half are essential and must be acquired from the nutrition. Absorption of amino acids is mediated by a set of amino acid transporters together with transport of di- and tripeptides. They provide amino acids for systemic needs and for enterocyte metabolism. Absorption is largely complete at the end of the small intestine. The large intestine mediates the uptake of amino acids derived from bacterial metabolism and endogenous sources. Lack of amino acid transporters and peptide transporter delays the absorption of amino acids and changes sensing and usage of amino acids by the intestine. This can affect metabolic health through amino acid restriction, sensing of amino acids, and production of antimicrobial peptides. Expected final online publication date for the Annual Review of Nutrition, Volume 43 is August 2023. Please see for revised estimates.
  9. Cell Rep. 2023 Jun 06. pii: S2211-1247(23)00628-9. [Epub ahead of print]42(6): 112617
      Neutrophil aggregation and clearance are important factors affecting neuroinflammatory injury during acute ischemic stroke. Emerging evidence suggests that energy metabolism is essential for microglial functions, especially microglial phagocytosis, which determines the degree of brain injury. Here, we demonstrate that Resolvin D1 (RvD1), a lipid mediator derived from docosahexaenic acid (DHA), promotes the phagocytosis of neutrophils by microglia, thereby reducing neutrophil accumulation in the brain and alleviating neuroinflammation in the ischemic brain. Further studies reveal that RvD1 reprograms energy metabolism from glycolysis to oxidative phosphorylation (OXPHOS), providing sufficient energy for microglial phagocytosis. Moreover, RvD1 enhances microglial glutamine uptake and stimulates glutaminolysis to support OXPHOS to boost ATP production depending on adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) activation. Overall, our results reveal that RvD1 reprograms energy metabolism to promote the microglial phagocytosis of neutrophils after ischemic stroke. These findings may guide perspectives for stroke therapy from modulating microglial immunometabolism.
    Keywords:  CP: Immunology; Resolvin D1; immunometabolism; ischemic stroke; microglia; neutrophil; phagocytosis; reprogram energy metabolism
  10. Cancer Biol Med. 2023 Jun 05. pii: j.issn.2095-3941.2022.0714. [Epub ahead of print]
      Prostate cancer, one of the most frequently occurring cancers in men, is a heterogeneous disease involving multiple cell types within tumors. This tumor heterogeneity at least partly results from genomic instability leading to sub-clonal cellular differentiation. The differentiated cell populations originate from a small subset of cells with tumor-initiating and stem-like properties. These cells, termed prostate cancer stem cells (PCSCs), play crucial roles in disease progression, drug resistance, and relapse. This review discusses the origin, hierarchy, and plasticity of PCSCs; methods for isolation and enrichment of PCSCs; and various cellular and metabolic signaling pathways involved in PCSC induction and maintenance, as well as therapeutic targeting.
    Keywords:  Epithelial-mesenchymal transition; cancer stem cells; metastasis; prostate cancer; signaling; tumor growth; tumor microenvironment
  11. Neurooncol Adv. 2023 Jan-Dec;5(1):5(1): vdad053
      Isocitrate dehydrogenase (IDH) is a key enzyme in normal metabolism and homeostasis. However, mutant forms of IDH are also defining features of a subset of diffuse gliomas. In this review, we highlight current techniques targeting IDH-mutated gliomas and summarize current and completed clinical trials exploring these strategies. We discuss clinical data from peptide vaccines, mutant IDH (mIDH) inhibitors, and PARP inhibitors. Peptide vaccines have the unique advantage of targeting the specific epitope of a patient's tumor, inducing a highly tumor-specific CD4+ T-cell response. mIDH-inhibitors, on the other hand, specifically target mutant IDH proteins in cancer cell metabolism and thus help halt gliomagenesis. We also explore PARP inhibitors and their role in treating diffuse gliomas, which exploit IDH-mutant diffuse gliomas by allowing the persistence of unrepaired DNA complexes. We summarize various completed and current trials targeting IDH1 and IDH2 mutations in diffuse gliomas. Therapies targeting mutant IDH have significant promise in treating progressive or recurrent IDH-mutant gliomas and may significantly change treatment paradigms in the next decade.
    Keywords:  IDH inhibitors; IDH mutation; glioma; isocitrate dehydrogenase; peptide vaccine