bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2023–01–15
eightteen papers selected by
Sreeparna Banerjee, Middle East Technical University
  1. The role of glutamine metabolism in castration-resistant prostate cancer.
  2. Overview of Cancer Metabolism and Signaling Transduction.
  3. Targeting cancer-specific metabolic pathways for developing novel cancer therapeutics.
  4. M2 macrophage-derived exosomal miR-193b-3p promotes progression and glutamine uptake of pancreatic cancer by targeting TRIM62.
  5. SMYD2 Promotes Hepatocellular Carcinoma Progression by Reprogramming Glutamine Metabolism via c-Myc/GLS1 Axis.
  6. IDH2 stabilizes HIF-1α-induced metabolic reprogramming and promotes chemoresistance in urothelial cancer.
  7. Glutamine Produces Ammonium to Tune Lysosomal pH and Regulate Lysosomal Function.
  8. High-throughput in situ perturbation of metabolite levels in the tumor micro-environment reveals favorable metabolic condition for increased fitness of infiltrated T-cells.
  9. Landscape and clinical impact of metabolic alterations in non-squamous non-small cell lung cancer.
  10. Probing Folate-Responsive and Stage-Sensitive Metabolomics and Transcriptional Co-Expression Network Markers to Predict Prognosis of Non-Small Cell Lung Cancer Patients.
  11. The Effect of Oxidative Phosphorylation on Cancer Drug Resistance.
  12. Clinical Significance of Glycolytic Metabolic Activity in Hepatocellular Carcinoma.
  13. Metabolic reprogramming and its clinical implication for liver cancer.
  14. Glutamine synthetase regulates the immune microenvironment and cancer development through the inflammatory pathway.
  15. Battles against aberrant KEAP1-NRF2 signaling in lung cancer: intertwined metabolic and immune networks.
  16. Improved antitumor activity against prostate cancer via synergistic targeting of Myc and GFAT-1.
  17. Metabolites as signalling molecules.
  18. A Review on Metabolic Paradoxes and their Impact on Metabolism.
  1. Asian J Androl. 2023 Jan 10.
    The role of glutamine metabolism in castration-resistant prostate cancer.
    Bing Zhao, Jing Wang, Li Chen, Hong Wang, Chao-Zhao Liang, Jiaoti Huang, Ling-Fan Xu.
      Reprogramming of metabolism is a hallmark of tumors, which has been explored for therapeutic purposes. Prostate cancer (PCa), particularly advanced and therapy-resistant PCa, displays unique metabolic properties. Targeting metabolic vulnerabilities in PCa may benefit patients who have exhausted currently available treatment options and improve clinical outcomes. Among the many nutrients, glutamine has been shown to play a central role in the metabolic reprogramming of advanced PCa. In addition to amino acid metabolism, glutamine is also widely involved in the synthesis of other macromolecules and biomasses. Targeting glutamine metabolic network by maximally inhibiting glutamine utilization in tumor cells may significantly add to treatment options for many patients. This review summarizes the metabolic landscape of PCa, with a particular focus on recent studies of how glutamine metabolism alterations affect therapeutic resistance and disease progression of PCa, and suggests novel therapeutic strategies.
    Keywords:  castration resistance; glutamine metabolism; prostate cancer; tumor metabolism
    DOI:  https://doi.org/10.4103/aja2022105
  2. Int J Mol Sci. 2022 Dec 20. pii: 12. [Epub ahead of print]24(1):
    Overview of Cancer Metabolism and Signaling Transduction.
    Hee-Suk Chae, Seong-Tshool Hong.
      Despite the remarkable progress in cancer treatment up to now, we are still far from conquering the disease. The most substantial change after the malignant transformation of normal cells into cancer cells is the alteration in their metabolism. Cancer cells reprogram their metabolism to support the elevated energy demand as well as the acquisition and maintenance of their malignancy, even in nutrient-poor environments. The metabolic alterations, even under aerobic conditions, such as the upregulation of the glucose uptake and glycolysis (the Warburg effect), increase the ROS (reactive oxygen species) and glutamine dependence, which are the prominent features of cancer metabolism. Among these metabolic alterations, high glutamine dependency has attracted serious attention in the cancer research community. In addition, the oncogenic signaling pathways of the well-known important genetic mutations play important regulatory roles, either directly or indirectly, in the central carbon metabolism. The identification of the convergent metabolic phenotypes is crucial to the targeting of cancer cells. In this review, we investigate the relationship between cancer metabolism and the signal transduction pathways, and we highlight the recent developments in anti-cancer therapy that target metabolism.
    Keywords:  ROS; aerobic glycolysis; anti-cancer drug; cancer; glutamine; metabolism; redox; signal transduction
    DOI:  https://doi.org/10.3390/ijms24010012
  3. Front Immunol. 2022 ;13 955476
    Targeting cancer-specific metabolic pathways for developing novel cancer therapeutics.
    Soumik Pal, Amit Sharma, Sam Padalumavunkal Mathew, Bithiah Grace Jaganathan.
      Cancer is a heterogeneous disease characterized by various genetic and phenotypic aberrations. Cancer cells undergo genetic modifications that promote their proliferation, survival, and dissemination as the disease progresses. The unabated proliferation of cancer cells incurs an enormous energy demand that is supplied by metabolic reprogramming. Cancer cells undergo metabolic alterations to provide for increased energy and metabolite requirement; these alterations also help drive the tumor progression. Dysregulation in glucose uptake and increased lactate production via "aerobic glycolysis" were described more than 100 years ago, and since then, the metabolic signature of various cancers has been extensively studied. However, the extensive research in this field has failed to translate into significant therapeutic intervention, except for treating childhood-ALL with amino acid metabolism inhibitor L-asparaginase. Despite the growing understanding of novel metabolic alterations in tumors, the therapeutic targeting of these tumor-specific dysregulations has largely been ineffective in clinical trials. This chapter discusses the major pathways involved in the metabolism of glucose, amino acids, and lipids and highlights the inter-twined nature of metabolic aberrations that promote tumorigenesis in different types of cancer. Finally, we summarise the therapeutic interventions which can be used as a combinational therapy to target metabolic dysregulations that are unique or common in blood, breast, colorectal, lung, and prostate cancer.
    Keywords:  cancer; cancer metabolism; cancer microenvironment; metabolic reprogramming; targeted therapy
    DOI:  https://doi.org/10.3389/fimmu.2022.955476
  4. Biol Direct. 2023 Jan 11. 18(1): 1
    M2 macrophage-derived exosomal miR-193b-3p promotes progression and glutamine uptake of pancreatic cancer by targeting TRIM62.
    Ke Zhang, Yu-Jie Li, Lin-Jia Peng, Hui-Feng Gao, Lu-Ming Liu, Hao Chen.
       BACKGROUND: Pancreatic cancer (PC) is a highly lethal malignancy that requires effective novel therapies. M2 macrophages are abundant in the PC microenvironment and promote cancer progression. Exosomes are emerging mediators of the crosstalk between cancer cells and the microenvironment. This study was conducted to explore the role of M2 macrophage-derived exosomes in PC.
    METHODS: Exosomes derived from M2 macrophages were extracted. miR-193b-3p and TRIM62 were overexpressed or silenced to examine their function in PC. Luminescence assays were used to investigate the interaction between miR-193b-3p and TRIM62. Cell proliferation was examined by EdU staining. Would healing and transwell assays were applied to evaluate cell migration and invasion. Co-immunoprecipitation was used to assess the interaction between TRIM62 and c-Myc. Gene and protein expressions were analyzed by quantitative RT-PCR and immunoblotting, respectively.
    RESULTS: M2 macrophage-derived exosomal miR-193b-3p promoted the proliferation, migration, invasion, and glutamine uptake of SW1990 cells. Mechanism study revealed that TRIM62 is a target of miR-193b-3p. TRIM62 inhibited the proliferation, migration, invasion, and glutamine uptake of SW1990 cells by promoting c-Myc ubiquitination. Our data also suggested that TRIM62 expression negatively correlated with miR-193b-3p and c-Myc expression. High-expression of miR-193b-3p and c-Myc predicts poor prognosis, whereas low-expression of TRIM62 predicts poor prognosis in patients with PC.
    CONCLUSION: M2 macrophage-derived exosomal miR-193b-3p enhances the proliferation, migration, invasion, and glutamine uptake of PC cells by targeting TRIM62, resulting in the decrease of c-Myc ubiquitination. This study not only reveals the mechanism underlying the crosstalk between M2 macrophages and PC cells but also suggests a promising therapeutic target for PC.
    Keywords:  Exosome; Glutamine metabolism; Macrophage; MiRNA; Pancreatic cancer
    DOI:  https://doi.org/10.1186/s13062-023-00356-y
  5. Cells. 2022 Dec 21. pii: 25. [Epub ahead of print]12(1):
    SMYD2 Promotes Hepatocellular Carcinoma Progression by Reprogramming Glutamine Metabolism via c-Myc/GLS1 Axis.
    Kangdi Xu, Jun Ding, Lingfeng Zhou, Dazhi Li, Jia Luo, Wenchao Wang, Mingge Shang, Bingyi Lin, Lin Zhou, Shusen Zheng.
      Metabolic reprogramming, such as alterations in glutamine metabolism or glycolysis, is the hallmark of hepatocellular carcinoma (HCC). However, the underlying mechanisms are still incompletely elucidated. Previous studies have identified that methyltransferase SET and MYND domain-containing protein 2(SMYD2) is responsible for the pathogenesis of numerous types of cancer. Here, we innovatively uncover how SMYD2 regulates glutamine metabolism in HCC cells and promotes HCC progression. We identified that SMYD2 expression is upregulated in HCC tissues, which correlates with unfavorable clinical outcomes. Our in vitro and in vivo results showed that the depletion of SMYD2 inhibits HCC cell growth. Mechanistically, c-Myc methylation by SMYD2 increases its protein stability through the ubiquitin-proteasome system. We showed SMYD2 depletion destabilized c-Myc protein by increasing the conjugated K48-linked polyubiquitin chain. SMYD2 increased c-Myc expression and further upregulated glutaminase1 (GLS1), a crucial enzyme that catalyzes the conversion of glutamine to glutamic acid, in HCC cells. GLS1 plays an important role in SMYD2-mediated HCC progression and glutamine metabolism regulation. The knockdown of SMYD2 inhibited glutamine metabolism in HCC cells and overcame their chemoresistance to sorafenib. Collectively, our findings demonstrated a novel mechanism of how SMYD2 promotes HCC progression by regulating glutamine metabolism through the c-Myc/GLS1signaling, implicating the therapeutic potential of targeting SMYD2 in HCC patients.
    Keywords:  GLS1; SMYD2; c-Myc; hepatocellular carcinoma
    DOI:  https://doi.org/10.3390/cells12010025
  6. EMBO J. 2023 Jan 13. e110620
    IDH2 stabilizes HIF-1α-induced metabolic reprogramming and promotes chemoresistance in urothelial cancer.
    Keisuke Shigeta, Masanori Hasegawa, Takako Hishiki, Yoshiko Naito, Yuto Baba, Shuji Mikami, Kazuhiro Matsumoto, Ryuichi Mizuno, Akira Miyajima, Eiji Kikuchi, Hideyuki Saya, Takeo Kosaka, Mototsugu Oya.
      Drug resistance contributes to poor therapeutic response in urothelial carcinoma (UC). Metabolomic analysis suggested metabolic reprogramming in gemcitabine-resistant urothelial carcinoma cells, whereby increased aerobic glycolysis and metabolic stimulation of the pentose phosphate pathway (PPP) promoted pyrimidine biosynthesis to increase the production of the gemcitabine competitor deoxycytidine triphosphate (dCTP) that diminishes its therapeutic effect. Furthermore, we observed that gain-of-function of isocitrate dehydrogenase 2 (IDH2) induced reductive glutamine metabolism to stabilize Hif-1α expression and consequently stimulate aerobic glycolysis and PPP bypass in gemcitabine-resistant UC cells. Interestingly, IDH2-mediated metabolic reprogramming also caused cross resistance to CDDP, by elevating the antioxidant defense via increased NADPH and glutathione production. Downregulation or pharmacological suppression of IDH2 restored chemosensitivity. Since the expression of key metabolic enzymes, such as TIGAR, TKT, and CTPS1, were affected by IDH2-mediated metabolic reprogramming and related to poor prognosis in patients, IDH2 might become a new therapeutic target for restoring chemosensitivity in chemo-resistant urothelial carcinoma.
    Keywords:  chemoresistance; hypoxia-inducible factor-1α; isocitrate dehydrogenase 2; metabolomic reprogramming; urothelial carcinoma
    DOI:  https://doi.org/10.15252/embj.2022110620
  7. Cells. 2022 Dec 24. pii: 80. [Epub ahead of print]12(1):
    Glutamine Produces Ammonium to Tune Lysosomal pH and Regulate Lysosomal Function.
    Jian Xiong, Thi Thu Trang Luu, Kartik Venkatachalam, Guangwei Du, Michael X Zhu.
      Glutamine is one of the most abundant amino acids in the cell. In mitochondria, glutaminases 1 and 2 (GLS1/2) hydrolyze glutamine to glutamate, which serves as the precursor of multiple metabolites. Here, we show that ammonium generated during GLS1/2-mediated glutaminolysis regulates lysosomal pH and in turn lysosomal degradation. In primary human skin fibroblasts BJ cells and mouse embryonic fibroblasts, deprivation of total amino acids for 1 h increased lysosomal degradation capacity as shown by the increased turnover of lipidated microtubule-associated proteins 1A/1B light chain 3B (LC3-II), several autophagic receptors, and endocytosed DQ-BSA. Removal of glutamine but not any other amino acids from the culture medium enhanced lysosomal degradation similarly as total amino acid starvation. The presence of glutamine in regular culture media increased lysosomal pH by >0.5 pH unit and the removal of glutamine caused lysosomal acidification. GLS1/2 knockdown, GLS1 antagonist, or ammonium scavengers reduced lysosomal pH in the presence of glutamine. The addition of glutamine or NH4Cl prevented the increase in lysosomal degradation and curtailed the extension of mTORC1 function during the early time period of amino acid starvation. Our findings suggest that glutamine tunes lysosomal pH by producing ammonium, which regulates lysosomal degradation to meet the demands of cellular activities. During the early stage of amino acid starvation, the glutamine-dependent mechanism allows more efficient use of internal reserves and endocytosed proteins to extend mTORC1 activation such that the normal anabolism is not easily interrupted by a brief disruption of the amino acid supply.
    Keywords:  amino acid starvation; autophagosome; autophagy; glutaminase; glutamine; lysosomal pH; mTORC1 activation
    DOI:  https://doi.org/10.3390/cells12010080
  8. Front Cell Dev Biol. 2022 ;10 1032360
    High-throughput in situ perturbation of metabolite levels in the tumor micro-environment reveals favorable metabolic condition for increased fitness of infiltrated T-cells.
    Veronica Valvo, Elena Parietti, Kyle Deans, Sebastian W Ahn, Noel Ruth Park, Benjamin Ferland, Devon Thompson, Christine Dominas, Sharath K Bhagavatula, Shawn Davidson, Oliver Jonas.
      Tumor-infiltrating immune cells experience significant metabolic reprogramming in the tumor microenvironment (TME), and they share similar metabolic pathways and nutrient needs with malignant cells. This positions these cell types in direct nutrient competition in the TME. We currently lack a complete understanding of the similarities, differences, and functional consequences of the metabolic pathways utilized by activated immune cells from different lineages versus neoplastic cells. This study applies a novel in situ approach using implantable microdevices to expose the tumor to 27 controlled and localized metabolic perturbations in order to perform a systematic investigation into the metabolic regulation of the cellular fitness and persistence between immune and tumor cells directly within the native TME. Our findings identify the most potent metabolites, notably glutamine and arginine, that induce a favorable metabolic immune response in a mammary carcinoma model, and reveal novel insights on less characterized pathways, such as cysteine and glutathione. We then examine clinical samples from cancer patients to confirm the elevation of these pathways in tumor regions that are enriched in activated T cells. Overall, this work provides the first instance of a highly multiplexed in situ competition assay between malignant and immune cells within tumors using a range of localized microdose metabolic perturbations. The approach and findings may be used to potentiate the effects of T cell stimulating immunotherapies on a tumor-specific or personalized basis through targeted enrichment or depletion of specific metabolites.
    Keywords:  T-cells infiltration; cancer metabolism; immunometabolism; immunotherapy; in situ perturbation; tumor micro-environment
    DOI:  https://doi.org/10.3389/fcell.2022.1032360
  9. Transl Lung Cancer Res. 2022 Dec;11(12): 2464-2476
    Landscape and clinical impact of metabolic alterations in non-squamous non-small cell lung cancer.
    Anna V Ivanina Foureau, Wei Sha, David M Foureau, James T Symanowski, Carol J Farhangfar, Kathryn F Mileham.
       Background: Metabolomics studies to date have described widespread metabolic reprogramming events during the development of non-squamous non-small cell lung cancer (NSCLC). Extending far beyond the Warburg effect, not only is carbohydrate metabolism affected, but also metabolism of amino acids, cofactors, lipids, and nucleotides.
    Methods: We evaluated the clinical impact of metabolic reprogramming. We performed comparative analysis of publicly available data on non-squamous NSCLC, to identify concensus altered metabolic pathways. We investigated whether alterations of metabolic genes controlling those consensus metabolic pathways impacted clinical outcome. Using the clinically annotated lung adenocarcinoma (LUAD) cohort from The Cancer Genome Atlas, we surveyed the distribution and frequency of function-altering mutations in metabolic genes and their impact on overall survival (OS).
    Results: We identified 42 metabolic genes of clinical significance, the majority of which (37 of 42) clustered across three metabolic superpathways (carbohydrates, amino acids, and nucleotides) and most functions (40 of 42) were associated with shorter OS. Multivariate analyses showed that dysfunction of carbohydrate metabolism had the most profound impact on OS [hazard ratio (HR) =5.208; 95% confidence interval (CI): 3.272 to 8.291], false discovery rate (FDR)-P≤0.0001, followed by amino acid metabolism (HR =3.346; 95% CI: 2.129 to 5.258), FDR-P≤0.0001 and nucleotide metabolism (HR =2.578; 95% CI: 1.598 to 4.159), FDR-P=0.0001. The deleterious effect of metabolic reprogramming on non-squamous NSCLC was observed independently of disease stage and across treatments groups.
    Conclusions: By providing a detailed landscape of metabolic alterations in non-squamous NSCLC, our findings offer new insights in the biology of the disease and metabolic adaptation mechanisms of clinical significance.
    Keywords:  Non-squamous non-small cell lung cancer; cancer metabolites; metabolic gene mutations; post-genomic pipeline
    DOI:  https://doi.org/10.21037/tlcr-22-377
  10. Nutrients. 2022 Dec 20. pii: 3. [Epub ahead of print]15(1):
    Probing Folate-Responsive and Stage-Sensitive Metabolomics and Transcriptional Co-Expression Network Markers to Predict Prognosis of Non-Small Cell Lung Cancer Patients.
    Yu-Shun Lin, Yen-Chu Chen, Tzu-En Chen, Mei-Ling Cheng, Ke-Shiuan Lynn, Pramod Shah, Jin-Shing Chen, Rwei-Fen S Huang.
      Tumour metabolomics and transcriptomics co-expression network as related to biological folate alteration and cancer malignancy remains unexplored in human non-small cell lung cancers (NSCLC). To probe the diagnostic biomarkers, tumour and pair lung tissue samples (n = 56) from 97 NSCLC patients were profiled for ultra-performance liquid chromatography tandem mass spectrometry (UPLC/MS/MS)-analysed metabolomics, targeted transcriptionomics, and clinical folate traits. Weighted Gene Co-expression Network Analysis (WGCNA) was performed. Tumour lactate was identified as the top VIP marker to predict advance NSCLC (AUC = 0.765, Sig = 0.017, CI 0.58-0.95). Low folate (LF)-tumours vs. adjacent lungs displayed higher glycolytic index of lactate and glutamine-associated amino acids in enriched biological pathways of amino sugar and glutathione metabolism specific to advance NSCLCs. WGCNA classified the green module for hub serine-navigated glutamine metabolites inversely associated with tumour and RBC folate, which module metabolites co-expressed with a predominant up-regulation of LF-responsive metabolic genes in glucose transport (GLUT1), de no serine synthesis (PHGDH, PSPH, and PSAT1), folate cycle (SHMT1/2 and PCFR), and down-regulation in glutaminolysis (SLC1A5, SLC7A5, GLS, and GLUD1). The LF-responsive WGCNA markers predicted poor survival rates in lung cancer patients, which could aid in optimizing folate intervention for better prognosis of NSCLCs susceptible to folate malnutrition.
    Keywords:  WGCNA; non–small-cell lung cancers; target metabolomics; transcriptional profile; tumour folate
    DOI:  https://doi.org/10.3390/nu15010003
  11. Cancers (Basel). 2022 Dec 22. pii: 62. [Epub ahead of print]15(1):
    The Effect of Oxidative Phosphorylation on Cancer Drug Resistance.
    Ziyi Zhao, Yong Mei, Ziyang Wang, Weiling He.
      Recent studies have shown that oxidative phosphorylation (OXPHOS) is a target for the effective attenuation of cancer drug resistance. OXPHOS inhibitors can improve treatment responses to anticancer therapy in certain cancers, such as melanomas, lymphomas, colon cancers, leukemias and pancreatic ductal adenocarcinoma (PDAC). However, the effect of OXPHOS on cancer drug resistance is complex and associated with cell types in the tumor microenvironment (TME). Cancer cells universally promote OXPHOS activity through the activation of various signaling pathways, and this activity is required for resistance to cancer therapy. Resistant cancer cells are prevalent among cancer stem cells (CSCs), for which the main metabolic phenotype is increased OXPHOS. CSCs depend on OXPHOS to survive targeting by anticancer drugs and can be selectively eradicated by OXPHOS inhibitors. In contrast to that in cancer cells, mitochondrial OXPHOS is significantly downregulated in tumor-infiltrating T cells, impairing antitumor immunity. In this review, we summarize novel research showing the effect of OXPHOS on cancer drug resistance, thereby explaining how this metabolic process plays a dual role in cancer progression. We highlight the underlying mechanisms of metabolic reprogramming in cancer cells, as it is vital for discovering new drug targets.
    Keywords:  cancer immunity; glycolysis; metabolism; oxidative phosphorylation; resistance
    DOI:  https://doi.org/10.3390/cancers15010062
  12. Cancers (Basel). 2022 Dec 28. pii: 186. [Epub ahead of print]15(1):
    Clinical Significance of Glycolytic Metabolic Activity in Hepatocellular Carcinoma.
    Joann Jung, Sowon Park, Yeonwoo Jang, Sung-Hwan Lee, Yun Seong Jeong, Sun Young Yim, Ju-Seog Lee.
      High metabolic activity is a hallmark of cancers, including hepatocellular carcinoma (HCC). However, the molecular features of HCC with high metabolic activity contributing to clinical outcomes and the therapeutic implications of these characteristics are poorly understood. We aimed to define the features of HCC with high metabolic activity and uncover its association with response to current therapies. By integrating gene expression data from mouse liver tissues and tumor tissues from HCC patients (n = 1038), we uncovered three metabolically distinct HCC subtypes that differ in clinical outcomes and underlying molecular biology. The high metabolic subtype is characterized by poor survival, the strongest stem cell signature, high genomic instability, activation of EPCAM and SALL4, and low potential for benefitting from immunotherapy. Interestingly, immune cell analysis showed that regulatory T cells (Tregs) are highly enriched in high metabolic HCC tumors, suggesting that high metabolic activity of cancer cells may trigger activation or infiltration of Tregs, leading to cancer cells' evasion of anti-cancer immune cells. In summary, we identified clinically and metabolically distinct subtypes of HCC, potential biomarkers associated with these subtypes, and a potential mechanism of metabolism-mediated immune evasion by HCC cells.
    Keywords:  Tregs; cancer metabolism; glycolysis; hepatocellular carcinoma; immunotherapy; liver cancer; stem cells; survival; transcriptome
    DOI:  https://doi.org/10.3390/cancers15010186
  13. Hepatology. 2023 Jan 03.
    Metabolic reprogramming and its clinical implication for liver cancer.
    Flora Yang, Leena Hilakivi-Clarke, Aurpita Shaha, Yuanguo Wang, Xianghu Wang, Yibin Deng, Jinping Lai, Ningling Kang.
      Cancer cells often encounter hypoxic and hypo-nutrient conditions, which force them to make adaptive changes to meet their high demands for energy and various biomaterials for biomass synthesis. As a result, enhanced catabolism (breakdown of macromolecules for energy production) and anabolism (macromolecule synthesis from bio-precursors) are induced in cancer. This phenomenon is called "metabolic reprogramming", a cancer hallmark contributing to cancer development, metastasis, and drug resistance. Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are two different liver cancers with high intertumoral heterogeneity in terms of etiologies, mutational landscapes, transcriptomes, and histological representations. In agreement, metabolism in HCC or CCA is remarkably heterogeneous, although changes in the glycolytic pathways and an increase in the generation of lactate (the Warburg effect) have been frequently detected in those tumors. For example, HCC tumors with activated β-catenin are addicted to fatty acid catabolism whereas HCC tumors derived from fatty liver avoid using fatty acids. In this review, we describe common metabolic alterations in HCC and CCA as well as metabolic features unique for their subsets. We discuss metabolism of non-alcoholic fatty liver disease (NAFLD) as well, because NAFLD will likely become a leading etiology of liver cancer in the coming years due to the obesity epidemic in the Western world. Furthermore, we outline the clinical implication of liver cancer metabolism and highlight the computation and systems biology approaches, such as genome-wide metabolic models, as a valuable tool allowing us to identify therapeutic targets and develop personalized treatments for liver cancer patients.
    DOI:  https://doi.org/10.1097/HEP.0000000000000005
  14. Int J Med Sci. 2023 ;20(1): 35-49
    Glutamine synthetase regulates the immune microenvironment and cancer development through the inflammatory pathway.
    Do Thi Minh Xuan, Chung-Che Wu, Wei-Jan Wang, Hui-Ping Hsu, Hoang Dang Khoa Ta, Gangga Anuraga, Chung-Chieh Chiao, Chih-Yang Wang.
      Although adjuvant tamoxifen therapy is beneficial to estrogen receptor-positive (ER+) breast cancer patients, a significant number of patients still develop metastasis or undergo recurrence. Therefore, identifying novel diagnostic and prognostic biomarkers for these patients is urgently needed. Predictive markers and therapeutic strategies for tamoxifen-resistant ER+ breast cancer are not clear, and micro (mi)RNAs have recently become a focal research point in cancer studies owing to their regulation of gene expressions, metabolism, and many other physiological processes. Therefore, systematic investigation is required to understand the modulation of gene expression in tamoxifen-resistant patients. High-throughput technology uses a holistic approach to observe differences among expression profiles of thousands of genes, which provides a comprehensive level to extensively investigate functional genomics and biological processes. Through a bioinformatics analysis, we revealed that glutamine synthetase/glutamate-ammonia ligase (GLUL) might play essential roles in the recurrence of tamoxifen-resistant ER+ patients. GLUL increases intracellular glutamine usage via glutaminolysis, and further active metabolism-related downstream molecules in cancer cell. However, how GLUL regulates the tumor microenvironment for tamoxifen-resistant ER+ breast cancer remains unexplored. Analysis of MetaCore pathway database demonstrated that GLUL is involved in the cell cycle, immune response, interleukin (IL)-4-induced regulators of cell growth, differentiation, and metabolism-related pathways. Experimental data also confirmed that the knockdown of GLUL in breast cancer cell lines decreased cell proliferation and influenced expressions of specific downstream molecules. Through a Connectivity Map (CMap) analysis, we revealed that certain drugs/molecules, including omeprazole, methacholine chloride, ioversol, fulvestrant, difenidol, cycloserine, and MK-801, may serve as potential treatments for tamoxifen-resistant breast cancer patients. These drugs may be tested in combination with current therapies in tamoxifen-resistant breast cancer patients. Collectively, our study demonstrated the crucial roles of GLUL, which provide new targets for the treatment of tamoxifen-resistant breast cancer patients.
    Keywords:  bioinformatics; breast cancer; glutamine synthetase (GLUL); immune microenvironment; tamoxifen
    DOI:  https://doi.org/10.7150/ijms.75625
  15. Theranostics. 2023 ;13(2): 704-723
    Battles against aberrant KEAP1-NRF2 signaling in lung cancer: intertwined metabolic and immune networks.
    Ke Xu, Jie Ma, Sean R R Hall, Ren-Wang Peng, Haitang Yang, Feng Yao.
      The Kelch-like ECH-associated protein 1/nuclear factor erythroid-derived 2-like 2 (KEAP1/NRF2) pathway is well recognized as a key regulator of redox homeostasis, protecting cells from oxidative stress and xenobiotics under physiological circumstances. Cancer cells often hijack this pathway during initiation and progression, with aberrant KEAP1-NRF2 activity predominantly observed in non-small cell lung cancer (NSCLC), suggesting that cell/tissue-of-origin is likely to influence the genetic selection during malignant transformation. Hyperactivation of NRF2 confers a multi-faceted role, and recently, increasing evidence shows that a close interplay between metabolic reprogramming and tumor immunity remodelling contributes to its aggressiveness, treatment resistance (radio-/chemo-/immune-therapy) and susceptibility to metastases. Here, we discuss in detail the special metabolic and immune fitness enabled by KEAP1-NRF2 aberration in NSCLC. Furthermore, we summarize the similarities and differences in the dysregulated KEAP1-NRF2 pathway between two major histo-subtypes of NSCLC, provide mechanistic insights on the poor response to immunotherapy despite their high immunogenicity, and outline evolving strategies to treat this recalcitrant cancer subset. Finally, we integrate bioinformatic analysis of publicly available datasets to illustrate the new partners/effectors in NRF2-addicted cancer cells, which may provide new insights into context-directed treatment.
    Keywords:  KEAP1-NRF2 signaling; bioinformatics; metabolic reprogramming; non-small cell lung cancer; therapeutic vulnerabilities; tumor immune microenvironment
    DOI:  https://doi.org/10.7150/thno.80184
  16. Theranostics. 2023 ;13(2): 578-595
    Improved antitumor activity against prostate cancer via synergistic targeting of Myc and GFAT-1.
    Yue Zhang, Jiang Li, Yixian Huang, Yuang Chen, Zhangyi Luo, Haozhe Huang, Raymond E West, Thomas D Nolin, Zhou Wang, Song Li.
      Inhibition of Myc promotes the regression of many types of tumors, including prostate cancer. However, the success of anti-Myc therapy is hampered by the lack of a strategy to effectively deliver the inhibitors to the tumor site and by the feedback mechanisms that cancer cells use to adapt to metabolic reprogramming. Methods: The effects of Myc inhibitors (10074-G5 or 10058-F4), alone or in combination with 6-diazo-5-oxo-L-norleucine (DON), were evaluated in cultured human or murine prostate cancer cells by cell viability assay, qRT-PCR and Western blot. To facilitate the in vivo therapeutic evaluation, a prodrug conjugate of 10074-G4 and DON (10074-DON) was developed, which could be effectively loaded into a polysaccharide-based nanocarrier (PS). Results: The treatment with Myc inhibitors led to significant induction of glutamine: fructose-6-phosphate amidotransferase-1 (GFAT1) and enhanced protein glycosylation. Mechanistically, Myc inhibition triggered GFAT1 induction through the IREα-Xbp1s pathway. The combination use of Myc inhibitors and GFAT1 inhibitor DON led to a synergistic effect in inhibiting the proliferation and migration of prostate cancer cells. Enhanced in vivo delivery of 10074-DON via the PS nanocarrier led to a significant inhibition of tumor growth along with an improvement in tumor immune microenvironment in several PCa animal models. Conclusion: Simultaneous targeting of Myc and GFAT-1 may represent a novel strategy for the treatment of prostate cancer.
    Keywords:  Myc; glutamine: fructose-6-phosphate amidotransferase-1; prostate cancer, therapy; protein glycosylation
    DOI:  https://doi.org/10.7150/thno.76614
  17. Nat Rev Mol Cell Biol. 2023 Jan 12.
    Metabolites as signalling molecules.
    Steven Andrew Baker, Jared Rutter.
      Traditional views of cellular metabolism imply that it is passively adapted to meet the demands of the cell. It is becoming increasingly clear, however, that metabolites do more than simply supply the substrates for biological processes; they also provide critical signals, either through effects on metabolic pathways or via modulation of other regulatory proteins. Recent investigation has also uncovered novel roles for several metabolites that expand their signalling influence to processes outside metabolism, including nutrient sensing and storage, embryonic development, cell survival and differentiation, and immune activation and cytokine secretion. Together, these studies suggest that, in contrast to the prevailing notion, the biochemistry of a cell is frequently governed by its underlying metabolism rather than vice versa. This important shift in perspective places common metabolites as key regulators of cell phenotype and behaviour. Yet the signalling metabolites, and the cognate targets and transducers through which they signal, are only beginning to be uncovered. In this Review, we discuss the emerging links between metabolism and cellular behaviour. We hope this will inspire further dissection of the mechanisms through which metabolic pathways and intermediates modulate cell function and will suggest possible drug targets for diseases linked to metabolic deregulation.
    DOI:  https://doi.org/10.1038/s41580-022-00572-w
  18. Arch Razi Inst. 2022 06;77(3): 929-941
    A Review on Metabolic Paradoxes and their Impact on Metabolism.
    A Gasmi, S Piscopo, A Menzel, S Noor.
      The current review paper portrays the important link of different nutrients like trace elements, proteins, fatty acids, vitamins, and amino acids with the immune system as well as information related to metabolic paradoxes. Optimum working of the metabolic system is essential because it gives various types of supplements to the human body and aid in chemical pathways. Here related data have been retrieved from two databases i.e., PubMed and Google scholar to grasp detailed knowledge about micronutrients and nutrients as well as their association in the metabolic system. Like protein play important role in the normal development of different immune components, amino acids including alanine, Arginine, and glutamic acid properly control the movement of neutrophils, macrophages, and cytokines. While fatty acids act as an anti-inflammatory agent because they possess the ability to inhibit the expression of the MHC class. Apart from these, many essential molecules like uric acid, proteins, calcium, lanolin are also obtained as end products after catabolic and anabolic reactions, and it was found that the uric acid paradox has a cancer inhibitory role. Additionally, TGF and IL-6 paradoxes have a role in the development of tumors, the onset of diabetes, and low-grade inflammatory disorders respectively. However, the entire functioning of metabolic processes depends upon daily diet because humans get the important nutrient from the diet which further vital role in the immune system. Moreover, it was also observed that calcium paradox is related to heart disorders because high calcium accumulation leads to cardiac disorders. Thus, the complete knowledge about these essential components as well as metabolic paradoxes is very important due to their antagonistic role to plan better and improved therapeutic strategies for various diseases.
    Keywords:   exercise; glutamine; metabolism; uric acid; vitamin C
    DOI:  https://doi.org/10.22092/ARI.2021.356277.1815
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