bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2023‒04‒09
twelve papers selected by
Sreeparna Banerjee
Middle East Technical University
  1. Targeting glutamine metabolism as a therapeutic strategy for cancer.
  2. Alone and together: current approaches to targeting glutaminase enzymes as part of anti-cancer therapies.
  3. Pancreatic Cancer Is Dependent on De Novo Ornithine Synthesis from Glutamine.
  4. Amino Acid Starvation-Induced Glutamine Accumulation Enhances Pneumococcal Survival.
  5. Postoperative parenteral glutamine supplementation improves the short-term outcomes in patients undergoing colorectal cancer surgery: A propensity score matching study.
  6. OXPHOS inhibitors, metabolism and targeted therapies in cancer.
  7. Integrated nontargeted and targeted metabolomics analyses amino acids metabolism in infantile hemangioma.
  8. A 211At-labelled mGluR1 inhibitor induces cancer senescence to elicit long-lasting anti-tumor efficacy.
  9. Design, synthesis, structure-activity relationship studies, and evaluation of novel GLS1 inhibitors.
  10. The role of amino acid metabolism alterations in pancreatic cancer: From mechanism to application.
  11. Circulating metabolites as potential biomarkers for the early detection and prognosis surveillance of gastrointestinal cancers.
  12. Quantification of Serum Metabolites in Early Colorectal Adenomas Using Isobaric Labeling Mass Spectrometry.
  1. Exp Mol Med. 2023 Apr 03.
    Targeting glutamine metabolism as a therapeutic strategy for cancer.
    Jonghwa Jin, Jun-Kyu Byun, Yeon-Kyung Choi, Keun-Gyu Park.
      Proliferating cancer cells rely largely on glutamine for survival and proliferation. Glutamine serves as a carbon source for the synthesis of lipids and metabolites via the TCA cycle, as well as a source of nitrogen for amino acid and nucleotide synthesis. To date, many studies have explored the role of glutamine metabolism in cancer, thereby providing a scientific rationale for targeting glutamine metabolism for cancer treatment. In this review, we summarize the mechanism(s) involved at each step of glutamine metabolism, from glutamine transporters to redox homeostasis, and highlight areas that can be exploited for clinical cancer treatment. Furthermore, we discuss the mechanisms underlying cancer cell resistance to agents that target glutamine metabolism, as well as strategies for overcoming these mechanisms. Finally, we discuss the effects of glutamine blockade on the tumor microenvironment and explore strategies to maximize the utility of glutamine blockers as a cancer treatment.
    DOI:  https://doi.org/10.1038/s12276-023-00971-9
  2. Future Drug Discov. 2023 Mar;4(4): FDD79
    Alone and together: current approaches to targeting glutaminase enzymes as part of anti-cancer therapies.
    Thuy-Tien T Nguyen, William P Katt, Richard A Cerione.
      Metabolic reprogramming is a major hallmark of malignant transformation in cancer, and part of the so-called Warburg effect, in which the upregulation of glutamine catabolism plays a major role. The glutaminase enzymes convert glutamine to glutamate, which initiates this pathway. Inhibition of different forms of glutaminase (KGA, GAC, or LGA) demonstrated potential as an emerging anti-cancer therapeutic strategy. The regulation of these enzymes, and the molecular basis for their inhibition, have been the focus of much recent research. This review will explore the recent progress in understanding the molecular basis for activation and inhibition of different forms of glutaminase, as well as the recent focus on combination therapies of glutaminase inhibitors with other anti-cancer drugs.
    Keywords:  Warburg effect; anti-cancer drugs; cancer; cell metabolism; crystallography; glutaminase; medicinal chemistry; structure-function
    DOI:  https://doi.org/10.4155/fdd-2022-0011
  3. Cancer Discov. 2023 Apr 07. OF1
    Pancreatic Cancer Is Dependent on De Novo Ornithine Synthesis from Glutamine.
      Polyamine synthesis in pancreatic cancer cells is dependent on de novo ornithine synthesis from glutamine.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2023-053
  4. mSphere. 2023 Apr 05. e0062522
    Amino Acid Starvation-Induced Glutamine Accumulation Enhances Pneumococcal Survival.
    Chengwang Zhang, Yanhong Liu, Haoran An, Xueying Wang, Lina Xu, Haiteng Deng, Songquan Wu, Jing-Ren Zhang, Xiaohui Liu.
      Bacteria are known to cope with amino acid starvation by the stringent response signaling system, which is mediated by the accumulation of the (p)ppGpp alarmones when uncharged tRNAs stall at the ribosomal A site. While a number of metabolic processes have been shown to be regulatory targets of the stringent response in many bacteria, the global impact of amino acid starvation on bacterial metabolism remains obscure. This work reports the metabolomic profiling of the human pathogen Streptococcus pneumoniae under methionine starvation. Methionine limitation led to the massive overhaul of the pneumococcal metabolome. In particular, methionine-starved pneumococci showed a massive accumulation of many metabolites such as glutamine, glutamic acid, lactate, and cyclic AMP (cAMP). In the meantime, methionine-starved pneumococci showed a lower intracellular pH and prolonged survival. Isotope tracing revealed that pneumococci depend predominantly on amino acid uptake to replenish intracellular glutamine but cannot convert glutamine to methionine. Further genetic and biochemical analyses strongly suggested that glutamine is involved in the formation of a "prosurvival" metabolic state by maintaining an appropriate intracellular pH, which is accomplished by the enzymatic release of ammonia from glutamine. Methionine starvation-induced intracellular pH reduction and glutamine accumulation also occurred to various extents under the limitation of other amino acids. These findings have uncovered a new metabolic mechanism of bacterial adaptation to amino acid limitation and perhaps other stresses, which may be used as a potential therapeutic target for infection control. IMPORTANCE Bacteria are known to cope with amino acid starvation by halting growth and prolonging survival via the stringent response signaling system. Previous investigations have allowed us to understand how the stringent response regulates many aspects of macromolecule synthesis and catabolism, but how amino acid starvation promotes bacterial survival at the metabolic level remains largely unclear. This paper reports our systematic profiling of the methionine starvation-induced metabolome in S. pneumoniae. To the best of our knowledge, this represents the first reported bacterial metabolome under amino acid starvation. These data have revealed that the significant accumulation of glutamine and lactate enables S. pneumoniae to form a "prosurvival" metabolic state with a lower intracellular pH, which inhibits bacterial growth for prolonged survival. Our findings have provided insightful information on the metabolic mechanisms of pneumococcal adaptation to nutrient limitation during the colonization of the human upper airway.
    Keywords:  Streptococcus pneumoniae; cellular pH; glutamine accumulation; intracellular pH; metabolome; methionine; methionine starvation; survival
    DOI:  https://doi.org/10.1128/msphere.00625-22
  5. Front Nutr. 2023 ;10 1040893
    Postoperative parenteral glutamine supplementation improves the short-term outcomes in patients undergoing colorectal cancer surgery: A propensity score matching study.
    Gang Tang, Feng Pi, Yu-Hao Qiu, Zheng-Qiang Wei.
      Introduction: The clinical utility of glutamine in patients undergoing colorectal cancer (CRC) surgery remains unclear. Therefore, we aimed to investigate the impact of postoperative treatment with glutamine on postoperative outcomes in patients undergoing CRC surgery.Methods: We included patients with CRC undergoing elective surgery between January 2014 and January 2021. Patients were divided into the glutamine and control groups. We retrospectively analyzed postoperative infections complications within 30 days and other outcomes using propensity score matching and performed between-group comparisons.
    Results: We included 1,004 patients who underwent CRC surgeries; among them, 660 received parenteral glutamine supplementation. After matching, there were 342 patients in each group. The overall incidence of postoperative complications was 14.9 and 36.8% in the glutamine and control groups, respectively, indicating that glutamine significantly reduced the incidence of postoperative complications [p < 0.001; risk ratio (RR) 0.41 [95% CI 0.30-0.54]]. Compared with the control group, the glutamine group had a significantly lower postoperative infection complications rate (10.5 vs. 28.9%; p < 0.001; RR 0.36 [95% CI 0.26-0.52]). Although there was no significant between-group difference in the time to first fluid diet (p = 0.052), the time to first defecation (p < 0.001), first exhaust (p < 0.001), and first solid diet (p < 0.001), as well as hospital stay (p < 0.001) were significantly shorter in the glutamine group than in the control group. Furthermore, glutamine supplementation significantly reduced the incidence of postoperative intestinal obstruction (p = 0.046). Moreover, glutamine supplementation alleviated the decrease in albumin (p < 0.001), total protein (p < 0.001), and prealbumin levels (p < 0.001).
    Conclusions: Taken together, postoperative parenteral glutamine supplementation can effectively reduce the incidence of postoperative complications, promote the recovery of intestinal function, and improve albumin levels in patients undergoing CRC surgery.
    Keywords:  albumin; colorectal cancer; glutamine; intestinal function; postoperative complications; propensity score
    DOI:  https://doi.org/10.3389/fnut.2023.1040893
  6. Biochem Pharmacol. 2023 Apr 03. pii: S0006-2952(23)00122-3. [Epub ahead of print]211 115531
    OXPHOS inhibitors, metabolism and targeted therapies in cancer.
    Octavia Cadassou, Lars Petter Jordheim.
      More and more studies highlight the complex metabolic characteristics and plasticity of cancer cells. To address these specificities and explore the associated vulnerabilities, new metabolism-targeting therapeutic strategies are being developed. It is more and more accepted that cancer cells do not produce their energy only from aerobic glycolysis, as some subtypes strongly rely on mitochondrial respiration (OXPHOS). This review focuses on classical and promising OXPHOS inhibitors (OXPHOSi), unravelling their interest and modes of actions in cancer, particularly in combination with other strategies. Indeed, in monotherapy, OXPHOSi display limited efficiency as they mostly trigger cell death in cancer cell subtypes that strongly depend on mitochondrial respiration and are not able to shift to other metabolic pathways to produce energy. Nevertheless, they remain very interesting in combination with conventional therapeutic strategies such as chemotherapy and radiotherapy, increasing their anti-tumoral actions. In addition, OXPHOSi can be included in even more innovative strategies such as combinations with other metabolic drugs or immunotherapies.
    Keywords:  Cancer metabolism; Drug combination; Immunotherapy; Metabolic plasticity; Mitochondrial respiration
    DOI:  https://doi.org/10.1016/j.bcp.2023.115531
  7. Front Oncol. 2023 ;13 1132344
    Integrated nontargeted and targeted metabolomics analyses amino acids metabolism in infantile hemangioma.
    Kaiying Yang, Tong Qiu, Xue Gong, Jiangyuan Zhou, Yuru Lan, Siyuan Chen, Yi Ji.
      Infantile hemangioma (IH) is the most common benign tumor in children. However, the exact pathogenesis of IH remains unclear. Integrated nontargeted and targeted metabolic analyses were performed to obtain insight into the possible pathogenic mechanism of IH. The results of nontargeted metabolic analysis showed that 216 and 128 differential metabolites (DMs) were identified between hemangioma-derived endothelial cells (HemECs) and HUVECs in positive-ion and negative-ion models, respectively. In both models, these DMs were predominantly enriched in pathways related to amino acid metabolism, including aminoacyl-tRNA biosynthesis and arginine and proline metabolism. Then, targeted metabolic analysis of amino acids was further performed to further clarify HemEC metabolism. A total of 22 amino acid metabolites were identified, among which only 16 metabolites, including glutamine, arginine and asparagine, were significantly differentially expressed between HemECs and HUVECs. These significant amino acids were significantly enriched in 10 metabolic pathways, including 'alanine, aspartate and glutamate metabolism', 'arginine biosynthesis', 'arginine and proline metabolism', and 'glycine, serine and threonine metabolism'. The results of our study revealed that amino acid metabolism is involved in IH. Key differential amino acid metabolites, including glutamine, asparagine and arginine, may play an important role in regulating HemEC metabolism.
    Keywords:  amino acids; hemangioma-derived endothelial cell; infantile hemangioma; nontargeted metabolic; targeted metabolic
    DOI:  https://doi.org/10.3389/fonc.2023.1132344
  8. Cell Rep Med. 2023 Mar 03. pii: S2666-3791(23)00052-6. [Epub ahead of print] 100960
    A 211At-labelled mGluR1 inhibitor induces cancer senescence to elicit long-lasting anti-tumor efficacy.
    Lin Xie, Lulu Zhang, Kuan Hu, Masayuki Hanyu, Yiding Zhang, Masayuki Fujinaga, Katsuyuki Minegishi, Takayuki Ohkubo, Kotaro Nagatsu, Cuiping Jiang, Takashi Shimokawa, Kazuma Ashisuke, Noriyuki Okonogi, Shigeru Yamada, Feng Wang, Rui Wang, Ming-Rong Zhang.
      Metabotropic glutamate receptor 1 (mGluR1), a key mediator of glutamatergic signaling, is frequently overexpressed in tumor cells and is an attractive drug target for most cancers. Here, we present a targeted radiopharmaceutical therapy strategy that antagonistically recognizes mGluR1 and eradicates mGluR1+ human tumors by harnessing a small-molecule alpha (α)-emitting radiopharmaceutical, 211At-AITM. A single dose of 211At-AITM (2.96 MBq) in mGluR1+ cancers exhibits long-lasting in vivo antitumor efficacy across seven subtypes of four of the most common tumors, namely, breast cancer, pancreatic cancer, melanoma, and colon cancers, with little toxicity. Moreover, complete regression of mGluR1+ breast cancer and pancreatic cancer is observed in approximate 50% of tumor-bearing mice. Mechanistically, the functions of 211At-AITM are uncovered in downregulating mGluR1 oncoprotein and inducing senescence of tumor cells with a reprogrammed senescence-associated secretory phenotype. Our findings suggest α-radiopharmaceutical therapy with 211At-AITM can be a useful strategy for mGluR1+ pan-cancers, regardless of their tissue of origin.
    Keywords:  (211)At-AITM; alpha-emitting radiopharmaceutical; glutamine metabolism; metabotropic glutamate receptor 1; oncoprotein; pan-cancer; reprogrammed senescence-associated secretory phenotype; senescence; targeted alpha radiopharmaceutical therapy; α−particle
    DOI:  https://doi.org/10.1016/j.xcrm.2023.100960
  9. Bioorg Med Chem Lett. 2023 Apr 01. pii: S0960-894X(23)00144-0. [Epub ahead of print]87 129266
    Design, synthesis, structure-activity relationship studies, and evaluation of novel GLS1 inhibitors.
    Michiko Jo, Keiichi Koizumi, Mizuho Suzuki, Daisuke Kanayama, Yurie Watanabe, Hiroaki Gouda, Hisashi Mori, Mineyuki Mizuguchi, Takayuki Obita, Yuko Nabeshima, Naoki Toyooka, Takuya Okada.
      Glutaminase converts glutamine into glutamic acid and has two isoforms: glutaminase 1 (GLS1) and glutaminase 2 (GLS2). GLS1 is overexpressed in several tumors, and research to develop glutaminase inhibitors as antitumor drugs is currently underway. The present study examined candidate GLS1 inhibitors using in silico screening and attempted to synthesize novel GLS1 inhibitors and assess their GLS1 inhibitory activities in a mouse kidney extract and against recombinant mouse and human GLS1. Novel compounds were synthesized using compound C as the lead compound, and their GLS1 inhibitory activities were evaluated using the mouse kidney extract. Among the derivatives tested, the trans-4-hydroxycyclohexylamide derivative 2j exhibited the strongest inhibitory activity. We also assessed the GLS1 inhibitory activities of the derivatives 2j, 5i, and 8a against recombinant mouse and human GLS1. The derivatives 5i and 8a significantly decreased the production of glutamic acid at 10 mM. In conclusion, we herein identified two compounds that exhibited GLS1 inhibitory activities with equal potencies as known GLS1 inhibitors. These results will contribute to the development of effective novel GLS1 inhibitors with more potent inhibitory activity.
    Keywords:  GLS1 inhibitor; Glutaminase; In silico screening; Structure–activity relationship
    DOI:  https://doi.org/10.1016/j.bmcl.2023.129266
  10. Biochim Biophys Acta Rev Cancer. 2023 Apr 02. pii: S0304-419X(23)00042-2. [Epub ahead of print] 188893
    The role of amino acid metabolism alterations in pancreatic cancer: From mechanism to application.
    Shenao Fu, Shaokang Xu, Shubing Zhang.
      The incidence of pancreatic cancer is increasing in both developed and developing Nations. In recent years, various research evidence suggested that reprogrammed metabolism may play a key role in pancreatic cancer tumorigenesis and development. Therefore, it has great potential as a diagnostic, prognostic and therapeutic target. Amino acid metabolism is deregulated in pancreatic cancer, and changes in amino acid metabolism can affect cancer cell status, systemic metabolism in malignant tumor patients and mistakenly involved in different biological processes including stemness, proliferation and growth, invasion and migration, redox state maintenance, autophagy, apoptosis and even tumor microenvironment interaction. Generally, the above effects are achieved through two pathways, energy metabolism and signal transduction. This review aims to highlight the current research progress on the abnormal alterations of amino acids metabolism in pancreatic cancer, how they affect tumorigenesis and development of pancreatic cancer and the application prospects of them as diagnostic, prognostic and therapeutic targets.
    Keywords:  Amino acid metabolism; Apoptosis; Autophagy; Cellular redox homeostasis; Pancreatic cancer; Tumor microenvironment; mTOR signaling
    DOI:  https://doi.org/10.1016/j.bbcan.2023.188893
  11. Metabolomics. 2023 Apr 04. 19(4): 36
    Circulating metabolites as potential biomarkers for the early detection and prognosis surveillance of gastrointestinal cancers.
    Guodong Song, Li Wang, Junlong Tang, Haohui Li, Shuyu Pang, Yan Li, Li Liu, Junyuan Hu.
      BACKGROUND AND AIMS: Two of the most lethal gastrointestinal (GI) cancers, gastric cancer (GC) and colon cancer (CC), are ranked in the top five cancers that cause deaths worldwide. Most GI cancer deaths can be reduced by earlier detection and more appropriate medical treatment. Unlike the current "gold standard" techniques, non-invasive and highly sensitive screening tests are required for GI cancer diagnosis. Here, we explored the potential of metabolomics for GI cancer detection and the classification of tissue-of-origin, and even the prognosis management.METHODS: Plasma samples from 37 gastric cancer (GC), 17 colon cancer (CC), and 27 non-cancer (NC) patients were prepared for metabolomics and lipidomics analysis by three MS-based platforms. Univariate, multivariate, and clustering analyses were used for selecting significant metabolic features. ROC curve analysis was based on a series of different binary classifications as well as the true-positive rate (sensitivity) and the false-positive rate (1-specificity).
    RESULTS: GI cancers exhibited obvious metabolic perturbation compared with benign diseases. The differentiated metabolites of gastric cancer (GC) and colon cancer (CC) were targeted to same pathways but with different degrees of cellular metabolism reprogramming. The cancer-specific metabolites distinguished the malignant and benign, and classified the cancer types. We also applied this test to before- and after-surgery samples, wherein surgical resection significantly altered the blood-metabolic patterns. There were 15 metabolites significantly altered in GC and CC patients who underwent surgical treatment, and partly returned to normal conditions.
    CONCLUSION: Blood-based metabolomics analysis is an efficient strategy for GI cancer screening, especially for malignant and benign diagnoses. The cancer-specific metabolic patterns process the potential for classifying tissue-of-origin in multi-cancer screening. Besides, the circulating metabolites for prognosis management of GI cancer is a promising area of research.
    Keywords:  Biomarker; Circulating metabolites; Colon cancer; Early detection; Gastric cancer; Metabolomics; Surveillance
    DOI:  https://doi.org/10.1007/s11306-023-02002-0
  12. J Proteome Res. 2023 Apr 04.
    Quantification of Serum Metabolites in Early Colorectal Adenomas Using Isobaric Labeling Mass Spectrometry.
    Yuan Liu, Hua Zhang, William F Dove, Zicong Wang, Zhijun Zhu, Perry J Pickhardt, Mark Reichelderfer, Lingjun Li.
      A major challenge in reducing the death rate of colorectal cancer is to screen patients using low-invasive testing. A blood test shows a high compliance rate with reduced invasiveness. In this work, a multiplex isobaric tag labeling strategy coupled with mass spectrometry is adopted to relatively quantify primary and secondary amine-containing metabolites in serum for the discovery of metabolite level changes of colorectal cancer. Serum samples from patients at different risk statuses and colorectal cancer growth statuses are studied. Metabolite identification is based on accurate mass matching and/or retention time of labeled metabolite standards. We quantify 40 metabolites across all the serum samples, including 18 metabolites validated with standards. We find significantly decreased levels of threonine and asparagine in the patients with growing adenomas or high-risk adenomas (p < 0.05). Glutamine levels decrease in patients with adenomas of unknown growth status or high-risk adenomas. In contrast, arginine levels are elevated in patients with low-risk adenoma. Receiver operating characteristic analysis shows high sensitivity and specificity of these metabolites for detecting growing adenomas. Based on these results, we conclude that a few metabolites identified here might contribute to distinguishing colorectal patients with growing adenomas from normal individuals and patients with unknown growth status of adenomas.
    Keywords:  colorectal cancer; isobaric tag; mass spectrometry; metabolomics; multiplex labeling; serum biomarker
    DOI:  https://doi.org/10.1021/acs.jproteome.3c00006
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