bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2023–02–19
fiveteen papers selected by
Sreeparna Banerjee, Middle East Technical University
  1. Targeting Glutamine Metabolism with a Novel Na+/K+-ATPase Inhibitor RX108 in Hepatocellular Carcinoma.
  2. Novel insight into metabolic reprogrammming in cancer radioresistance: A promising therapeutic target in radiotherapy.
  3. Glutamine is a substrate for glycosylation and CA19-9 biosynthesis through hexosamine biosynthetic pathway in pancreatic cancer.
  4. Xanthine dehydrogenase rewires metabolism and the survival of nutrient deprived lung adenocarcinoma cells by facilitating UPR and autophagic degradation.
  5. An Overview: The Diversified Role of Mitochondria in Cancer Metabolism.
  6. Mitochondrial metabolism in primary and metastatic human kidney cancers.
  7. Lactate-related metabolic reprogramming and immune regulation in colorectal cancer.
  8. Glucose deprivation promotes pseudo-hypoxia and de-differentiation in lung adenocarcinoma.
  9. Influenced tumor microenvironment and tumor immunity by amino acids.
  10. Correlation between the Warburg effect and progression of triple-negative breast cancer.
  11. Cell Survival Enabled by Leakage of a Labile Metabolic Intermediate.
  12. Dynamics of co-substrate pools can constrain and regulate metabolic fluxes.
  13. Identification of four metabolic subtypes and key prognostic markers in lung adenocarcinoma based on glycolytic and glutaminolytic pathways.
  14. Metabolic rearrangements and intratumoral heterogeneity for immune response in hepatocellular carcinoma.
  15. Glutathione supports lipid abundance in vivo.
  1. Mol Cancer Ther. 2023 Feb 10. pii: MCT-22-0490. [Epub ahead of print]
    Targeting Glutamine Metabolism with a Novel Na+/K+-ATPase Inhibitor RX108 in Hepatocellular Carcinoma.
    Daoyan Wei, Dongmei Chen, Hongyuan Mou, Sharmistha Chakraborty, Bo Wei, Lin Tan, Philip L Lorenzi, Xiangping Qian, Peiying Yang.
      The poor prognosis and limited therapeutic options for human hepatocellular carcinoma (HCC), the most common form of liver cancer, highlight the urgent need to identify novel therapeutic modalities. Here we describe the antitumor activity and underlying molecular mechanisms of a novel Na+/K+-ATPase inhibitor RX108 in human HCC cells and its xenograft model. RX108 dose-dependently inhibited HCC cell proliferation in vitro and tumor growth in a xenograft mouse model, and that the inhibition was associated with induction of apoptosis. Mechanistically, RX108 significantly downregulated alanine serine cysteine transporter 2 (ASCT2) protein expression and reduced glutamine and glutamate concentration in HCC cells and tumors. Additionally, RX108 exposure led to a significant decrease in cell energy metabolism in Huh7 and Hep3B cells, including decreased levels of glutathione, NADH, NADPH, and mitochondrial respiration oxygen consumption rate (OCR). Furthermore, HCC cells exhibited evidence of glutamine addiction; the antiproliferative effect of RX108 was dependent on glutamine transport. Clinically, elevated ASCT2 mRNA expression in HCCs was associated with unfavorable survival. Taken together, these findings reveal a novel approach to target glutamine metabolism through inhibiting Na+/K+-ATPase and provide a rationale for using RX108 to treat HCC in patients whose tumors express ASCT2 at high levels. RX108 is currently under clinical development.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-22-0490
  2. Int J Biol Sci. 2023 ;19(3): 811-828
    Novel insight into metabolic reprogrammming in cancer radioresistance: A promising therapeutic target in radiotherapy.
    Yilin Yu, Jie Yu, Shengfang Ge, Yun Su, Xianqun Fan.
      Currently, cancer treatment mainly consists of surgery, radiotherapy, chemotherapy, immunotherapy, and molecular targeted therapy, of which radiotherapy is one of the major pillars. However, the occurrence of radioresistance largely limits its therapeutic effect. Metabolic reprogramming is an important hallmark in cancer progression and treatment resistance. In radiotherapy, DNA breakage is the major mechanism of cell damage, and in turn, cancer cells are prone to increase the metabolic flux of glucose, glutamine, serine, arginine, fatty acids etc., thus providing sufficient substrates and energy for DNA damage repair. Therefore, studying the linkage between metabolic reprogramming and cancer radioresistance may provide new ideas for improving the efficacy of tumor therapy. This review mainly focuses on the role of metabolic alterations, including glucose, amino acid, lipid, nucleotide and other ion metabolism, in radioresistance, and proposes possible therapeutic targets to improve the efficacy of cancer radiotherapy.
    Keywords:  Cancer; Metabolic Reprogrammming; Radioresistance; Therapeutic Targets
    DOI:  https://doi.org/10.7150/ijbs.79928
  3. Discov Oncol. 2023 Feb 17. 14(1): 20
    Glutamine is a substrate for glycosylation and CA19-9 biosynthesis through hexosamine biosynthetic pathway in pancreatic cancer.
    Chen Liu, Shengming Deng, Zhiwen Xiao, Renquan Lu, He Cheng, Jingjing Feng, Xuxia Shen, Quanxing Ni, Weiding Wu, Xianjun Yu, Guopei Luo.
       BACKGROUND: Carbohydrate antigen 19-9 (CA19-9) is the most widely used biomarker for pancreatic cancer. Since CA19-9 closely correlates with patient outcome and tumor stage in pancreatic cancer, the deciphering of CA19-9 biosynthesis provides a potential clue for treatment.
    METHODS: Concentration of amino acids was detected by ultrahigh-performance liquid chromatography tandem mass spectrometry. Metabolic flux of glutamine was examined by isotope tracing untargeted metabolomics. Label-free quantitative N-glycosylation proteomics was used to examine N-glycosylation alterations.
    RESULTS: Among all amino acids, glutamine was higher in CA19-9-high pancreatic cancers (> 37 U/mL, 66 cases) than in CA19-9-normal clinical specimens (≤ 37 U/mL, 37 cases). The glutamine concentration in clinical specimens was positively correlated with liver metastasis or lymphovascular invasion. Glutamine blockade using diazooxonorleucine suppressed pancreatic cancer growth and intraperitoneal and lymphatic metastasis. Glutamine promotes O-GlcNAcylation, protein glycosylation, and CA19-9 biosynthesis through the hexosamine biosynthetic pathway. UDP-N-acetylglucosamine (UDP-GlcNAc) levels correlated with the glutamine influx through hexosamine biosynthetic pathway and supported CA19-9 biosynthesis.
    CONCLUSIONS: Glutamine is a substrate for CA19-9 biosynthesis in pancreatic cancer. Glutamine blockade may be a potential therapeutic strategy for pancreatic cancer.
    Keywords:  CA19-9; GlcNAc; Glucose; Glutamine; Pancreatic adenocarcinoma
    DOI:  https://doi.org/10.1007/s12672-023-00628-z
  4. Int J Biol Sci. 2023 ;19(3): 772-788
    Xanthine dehydrogenase rewires metabolism and the survival of nutrient deprived lung adenocarcinoma cells by facilitating UPR and autophagic degradation.
    Man-Man Chen, Wei Guo, Si-Meng Chen, Xiao-Zhen Guo, Lan Xu, Xiao-Yu Ma, Yu-Xiang Wang, Cen Xie, Ling-Hua Meng.
      Xanthine dehydrogenase (XDH) is the rate-limiting enzyme in purine catabolism by converting hypoxanthine to xanthine and xanthine to uric acid. The altered expression and activity of XDH are associated with the development and prognosis of multiple types of cancer, while its role in lung adenocarcinoma (LUAD) remains unknown. Herein, we demonstrated that XDH was highly expressed in LUAD and was significantly correlated with poor prognosis. Though inhibition of XDH displayed moderate effect on the viability of LUAD cells cultured in the complete medium, it significantly attenuated the survival of starved cells. Similar results were obtained in XDH-knockout cells. Nucleosides supplementation rescued the survival of starved LUAD cells upon XDH inhibition, while inhibition of purine nucleoside phosphorylase abrogated the process, indicating that nucleoside degradation is required for the XDH-mediated survival of LUAD cells. Accordingly, metabolic flux revealed that ribose derived from nucleoside fueled key carbon metabolic pathways to sustain the survival of starved LUAD cells. Mechanistically, down-regulation of XDH suppressed unfolded protein response (UPR) and autophagic flux in starved LUAD cells. Inhibition of XDH decreased the level of amino acids produced by autophagic degradation, which was accompanied with down-regulation of mTORC1 signaling. Supplementation of amino acids including glutamine or glutamate rescued the survival of starved LUAD cells upon knockout or inhibition of XDH. Finally, XDH inhibitors potentiated the anti-cancer activity of 2-deoxy-D-glucose that induced UPR and/or autophagy in vitro and in vivo. In summary, XDH plays a crucial role in the survival of starved LUAD cells and targeting XDH may improve the efficacy of drugs that induce UPR and autophagy in the therapy of LUAD.
    Keywords:  LUAD; UPR; Xanthine dehydrogenase; autophagy; cell survival; nucleoside degradation
    DOI:  https://doi.org/10.7150/ijbs.78948
  5. Int J Biol Sci. 2023 ;19(3): 897-915
    An Overview: The Diversified Role of Mitochondria in Cancer Metabolism.
    Yu'e Liu, Yihong Sun, Yadong Guo, Xiaoyun Shi, Xi Chen, Wenfeng Feng, Lei-Lei Wu, Jin Zhang, Shibo Yu, Yi Wang, Yufeng Shi.
      Mitochondria are intracellular organelles involved in energy production, cell metabolism and cell signaling. They are essential not only in the process of ATP synthesis, lipid metabolism and nucleic acid metabolism, but also in tumor development and metastasis. Mutations in mtDNA are commonly found in cancer cells to promote the rewiring of bioenergetics and biosynthesis, various metabolites especially oncometabolites in mitochondria regulate tumor metabolism and progression. And mutation of enzymes in the TCA cycle leads to the unusual accumulation of certain metabolites and oncometabolites. Mitochondria have been demonstrated as the target for cancer treatment. Cancer cells rely on two main energy resources: oxidative phosphorylation (OXPHOS) and glycolysis. By manipulating OXPHOS genes or adjusting the metabolites production in mitochondria, tumor growth can be restrained. For example, enhanced complex I activity increases NAD+/NADH to prevent metastasis and progression of cancers. In this review, we discussed mitochondrial function in cancer cell metabolism and specially explored the unique role of mitochondria in cancer stem cells and the tumor microenvironment. Targeting the OXPHOS pathway and mitochondria-related metabolism emerging as a potential therapeutic strategy for various cancers.
    Keywords:  cancer; mitochondria; tumor metabolism; tumor metastasis
    DOI:  https://doi.org/10.7150/ijbs.81609
  6. bioRxiv. 2023 Feb 07. pii: 2023.02.06.527285. [Epub ahead of print]
    Mitochondrial metabolism in primary and metastatic human kidney cancers.
    Divya Bezwada, Nicholas P Lesner, Bailey Brooks, Hieu S Vu, Zheng Wu, Ling Cai, Stacy Kasitinon, Sherwin Kelekar, Feng Cai, Arin B Aurora, McKenzie Patrick, Ashley Leach, Rashed Ghandour, Yuanyuan Zhang, Duyen Do, Jessica Sudderth, Dennis Dumesnil, Sara House, Tracy Rosales, Alan M Poole, Yair Lotan, Solomon Woldu, Aditya Bagrodia, Xiaosong Meng, Jeffrey A Cadeddu, Prashant Mishra, Ivan Pedrosa, Payal Kapur, Kevin D Courtney, Craig R Malloy, Vitaly Margulis, Ralph J DeBerardinis.
      Most kidney cancers display evidence of metabolic dysfunction 1â€"4 but how this relates to cancer progression in humans is unknown. We used a multidisciplinary approach to infuse 13 C-labeled nutrients during surgical tumour resection in over 70 patients with kidney cancer. Labeling from [U- 13 C]glucose varies across cancer subtypes, indicating that the kidney environment alone cannot account for all metabolic reprogramming in these tumours. Compared to the adjacent kidney, clear cell renal cell carcinomas (ccRCC) display suppressed labelling of tricarboxylic acid (TCA) cycle intermediates in vivo and in organotypic slices cultured ex vivo, indicating that suppressed labeling is tissue intrinsic. Infusions of [1,2- 13 C]acetate and [U- 13 C]glutamine in patients, coupled with respiratory flux of mitochondria isolated from kidney and tumour tissue, reveal primary defects in mitochondrial function in human ccRCC. However, ccRCC metastases unexpectedly have enhanced labeling of TCA cycle intermediates compared to primary ccRCCs, indicating a divergent metabolic program during ccRCC metastasis in patients. In mice, stimulating respiration in ccRCC cells is sufficient to promote metastatic colonization. Altogether, these findings indicate that metabolic properties evolve during human kidney cancer progression, and suggest that mitochondrial respiration may be limiting for ccRCC metastasis but not for ccRCC growth at the site of origin.
    DOI:  https://doi.org/10.1101/2023.02.06.527285
  7. Front Endocrinol (Lausanne). 2022 ;13 1089918
    Lactate-related metabolic reprogramming and immune regulation in colorectal cancer.
    Qianhui Sun, Jingyuan Wu, Guanghui Zhu, Tingting Li, Xiaoyu Zhu, Baoyi Ni, Bowen Xu, Xinyi Ma, Jie Li.
      Changes in cellular metabolism involving fuel sources are well-known mechanisms of cancer cell differentiation in the context of carcinogenesis. Metabolic reprogramming is regulated by oncogenic signaling and transcriptional networks and has been identified as an essential component of malignant transformation. Hypoxic and acidified tumor microenvironment contributes mainly to the production of glycolytic products known as lactate. Mounting evidence suggests that lactate in the tumor microenvironment of colorectal cancer(CRC) contributes to cancer therapeutic resistance and metastasis. The contents related to the regulatory effects of lactate on metabolism, immune response, and intercellular communication in the tumor microenvironment of CRC are also constantly updated. Here we summarize the latest studies about the pleiotropic effects of lactate in CRC and the clinical value of targeting lactate metabolism as treatment. Different effects of lactate on various immune cell types, microenvironment characteristics, and pathophysiological processes have also emerged. Potential specific therapeutic targeting of CRC lactate metabolism is also discussed. With increased knowledge, effective druggable targets might be identified, with the aim of improving treatment outcomes by reducing chemoresistance.
    Keywords:  colorectal cancer; immune response; immunoregulation; lactate; metabolic reprogramming
    DOI:  https://doi.org/10.3389/fendo.2022.1089918
  8. bioRxiv. 2023 Feb 01. pii: 2023.01.30.526207. [Epub ahead of print]
    Glucose deprivation promotes pseudo-hypoxia and de-differentiation in lung adenocarcinoma.
    Pasquale Saggese, Aparamita Pandey, Eileen Fung, Abbie Hall, Jane Yanagawa, Erika F Rodriguez, Tristan R Grogan, Giorgio Giurato, Giovanni Nassa, Annamaria Salvati, Alessandro Weisz, Steven M Dubinett, Claudio Scafoglio.
      Increased utilization of glucose is a hallmark of cancer. Several studies are investigating the efficacy of glucose restriction by glucose transporter blockade or glycolysis inhibition. However, the adaptations of cancer cells to glucose restriction are unknown. Here, we report the discovery that glucose restriction in lung adenocarcinoma (LUAD) induces cancer cell de-differentiation, leading to a more aggressive phenotype. Glucose deprivation causes a reduction in alpha-ketoglutarate (αKG), leading to attenuated activity of αKG-dependent histone demethylases and histone hypermethylation. We further show that this de-differentiated phenotype depends on unbalanced EZH2 activity, causing inhibition of prolyl-hydroxylase PHD3 and increased expression of hypoxia inducible factor 1α (HIF1α), triggering epithelial to mesenchymal transition. Finally, we identified an HIF1α-dependent transcriptional signature with prognostic significance in human LUAD. Our studies further current knowledge of the relationship between glucose metabolism and cell differentiation in cancer, characterizing the epigenetic adaptation of cancer cells to glucose deprivation and identifying novel targets to prevent the development of resistance to therapies targeting glucose metabolism.
    DOI:  https://doi.org/10.1101/2023.01.30.526207
  9. Front Immunol. 2023 ;14 1118448
    Influenced tumor microenvironment and tumor immunity by amino acids.
    Min Yu, Shuang Zhang.
      It is widely accepted that tumors are a complex tissue composed of cancer cells, extracellular matrix, inflammatory cells, immune cells, and other cells. Deregulation of tumor microenvironment promotes tumor aggressiveness by sustaining cell growth, invasion, and survival from immune surveillance. The concepts that some dietary nutrients could change tumor microenvironment are extremely attractive. Many studies demonstrated that high-fat diet-induced obesity shaped metabolism to suppress anti-tumor immunity, but how amino acids changed the tumor microenvironment and impacted tumor immunity was still not totally understood. In fact, amino acid metabolism in different signaling pathways and their cross-talk shaped tumor immunity and therapy efficacy in cancer patients. Our review focused on mechanisms by which amino acid influenced tumor microenvironment, and found potential drug targets for immunotherapy in cancer.
    Keywords:  T lymphocytes; amino acids; cancer cells; tumor immunity; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2023.1118448
  10. Front Oncol. 2022 ;12 1060495
    Correlation between the Warburg effect and progression of triple-negative breast cancer.
    Shaojun Liu, Yuxuan Li, Meng Yuan, Qing Song, Min Liu.
      Triple-negative breast cancer (TNBC) is ineligible for hormonal therapy and Her-2-targeted therapy due to the negative expression of the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2. Although targeted therapy and immunotherapy have been shown to attenuate the aggressiveness of TNBC partially, few patients have benefited from them. The conventional treatment for TNBC remains chemotherapy. Chemoresistance, however, impedes therapeutic progress over time, and chemotherapy toxicity increases the burden of cancer on patients. Therefore, introducing more advantageous TNBC treatment options is a necessity. Metabolic reprogramming centered on glucose metabolism is considered a hallmark of tumors. It is described as tumor cells tend to convert glucose to lactate even under normoxic conditions, a phenomenon known as the Warburg effect. Similar to Darwinian evolution, its emergence is attributed to the selective pressures formed by the hypoxic microenvironment of pre-malignant lesions. Of note, the Warburg effect does not disappear with changes in the microenvironment after the formation of malignant tumor phenotypes. Instead, it forms a constitutive expression mediated by mutations or epigenetic modifications, providing a robust selective survival advantage for primary and metastatic lesions. Expanding evidence has demonstrated that the Warburg effect mediates multiple invasive behaviors in TNBC, including proliferation, metastasis, recurrence, immune escape, and multidrug resistance. Moreover, the Warburg effect-targeted therapy has been testified to be feasible in inhibiting TNBC progression. However, not all TNBCs are sensitive to glycolysis inhibitors because TNBC cells flexibly switch their metabolic patterns to cope with different survival pressures, namely metabolic plasticity. Between the Warburg effect-targeted medicines and the actual curative effect, metabolic plasticity creates a divide that must be continuously researched and bridged.
    Keywords:  Warburg effect; basal-like breast cancer; glycolysis; metabolic plasticity; triple-negative breast cancer
    DOI:  https://doi.org/10.3389/fonc.2022.1060495
  11. Mol Biol Evol. 2023 Feb 15. pii: msad032. [Epub ahead of print]
    Cell Survival Enabled by Leakage of a Labile Metabolic Intermediate.
    Encarnación Medina-Carmona, Luis I Gutierrez-Rus, Fadia Manssour-Triedo, Matilda S Newton, Gloria Gamiz-Arco, Antonio J Mota, Pablo Reiné, Juan Manuel Cuerva, Mariano Ortega-Muñoz, Eduardo Andrés-León, Jose Luis Ortega-Roldan, Burckhard Seelig, Beatriz Ibarra-Molero, Jose M Sanchez-Ruiz.
      Many metabolites are generated in one step of a biochemical pathway and consumed in a subsequent step. Such metabolic intermediates are often reactive molecules which, if allowed to freely diffuse in the intracellular milieu, could lead to undesirable side reactions and even become toxic to the cell. Therefore, metabolic intermediates are often protected as protein-bound species and directly transferred between enzyme active sites in multi-functional enzymes, multi-enzyme complexes and metabolons. Sequestration of reactive metabolic intermediates thus contributes to metabolic efficiency. It is not known, however, whether this evolutionary adaptation can be relaxed in response to challenges to organismal survival. Here, we report evolutionary repair experiments on E. coli cells in which an enzyme crucial for the biosynthesis of proline has been deleted. The deletion makes cells unable to grow in a culture medium lacking proline. Remarkably, however, cell growth is efficiently restored by many single mutations (12 at least) in the gene of glutamine synthetase. The mutations cause the leakage to the intracellular milieu of a highly reactive phosphorylated intermediate common to the biosynthetic pathways of glutamine and proline. This intermediate is generally assumed to exist only as a protein-bound species. Nevertheless, its diffusion upon mutation-induced leakage enables a new route to proline biosynthesis. Our results support that leakage of sequestered metabolic intermediates can readily occur and contribute to organismal adaptation in some scenarios. Enhanced availability of reactive molecules may enable the generation of new biochemical pathways and the potential of mutation-induced leakage in metabolic engineering is noted.
    Keywords:  auxotrophy rescue; evolutionary repair experiments; labile metabolic intermediates; laboratory evolution; metabolic innovation; prototrophy restoration
    DOI:  https://doi.org/10.1093/molbev/msad032
  12. Elife. 2023 Feb 17. pii: e84379. [Epub ahead of print]12
    Dynamics of co-substrate pools can constrain and regulate metabolic fluxes.
    Robert West, Hadrien Delattre, Elad Noor, Elisenda Feliu, Orkun Soyer.
      Cycling of co-substrates, whereby a metabolite is converted among alternate forms via different reactions, is ubiquitous in metabolism. Several cycled co-substrates are well known as energy and electron carriers (e.g. ATP and NAD(P)H), but there are also other metabolites that act as cycled co-substrates in different parts of central metabolism. Here, we develop a mathematical framework to analyse the effect of co-substrate cycling on metabolic flux. In the cases of a single reaction and linear pathways, we find that co-substrate cycling imposes an additional flux limit on a reaction, distinct to the limit imposed by the kinetics of the primary enzyme catalysing that reaction. Using analytical methods, we show that this additional limit is a function of the total pool size and turnover rate of the cycled co-substrate. Expanding from this insight and using simulations, we show that regulation of these two parameters can allow regulation of flux dynamics in branched and coupled pathways. To support these theoretical insights, we analysed existing flux measurements and enzyme levels from the central carbon metabolism and identified several reactions that could be limited by the dynamics of co-substrate cycling. We discuss how the limitations imposed by co-substrate cycling provide experimentally testable hypotheses on specific metabolic phenotypes. We conclude that measuring and controlling co-substrate dynamics is crucial for understanding and engineering metabolic fluxes in cells.
    Keywords:  E. coli; computational biology; systems biology
    DOI:  https://doi.org/10.7554/eLife.84379
  13. BMC Cancer. 2023 Feb 13. 23(1): 152
    Identification of four metabolic subtypes and key prognostic markers in lung adenocarcinoma based on glycolytic and glutaminolytic pathways.
    Jinjin Zhang, Xiaopeng Wang, Congkuan Song, Qi Li.
       BACKGROUND: Glucose and glutamine are the main energy sources for tumor cells. Whether glycolysis and glutaminolysis play a critical role in driving the molecular subtypes of lung adenocarcinoma (LUAD) is unknown. This study attempts to identify LUAD metabolic subtypes with different characteristics and key genes based on gene transcription profiling data related to glycolysis and glutaminolysis, and to construct prognostic models to facilitate patient outcome prediction.
    METHODS: LUAD related data were obtained from the Cancer Genome Atlas and Gene Expression Omnibus, including TCGA-LUAD, GSE42127, GSE68465, GSE72094, GSE29013, GSE31210, GSE30219, GSE37745, GSE50081. Unsupervised consensus clustering was used for the identification of LUAD subtypes. Differential expression analysis, weighted gene co-expression network analysis (WGCNA) and CytoNCA App in Cytoscape 3.9.0 were used for the screening of key genes. The Cox proportional hazards model was used for the construction of the prognostic risk model. Finally, qPCR analysis, immunohistochemistry and immunofluorescence colocalization were used to validate the core genes of the model.
    RESULT: This study identified four distinct characterized LUAD metabolic subtypes, glycolytic, glutaminolytic, mixed and quiescent types. The glycolytic type had a worse prognosis than the glutaminolytic type. Nine genes (CXCL8, CNR1, AGER, ALB, S100A7, SLC2A1, TH, SPP1, LEP) were identified as hub genes driving the glycolytic/glutaminolytic LUAD. In addition, the risk assessment model constructed based on three genes (SPP1, SLC2A1 and AGER) had good predictive performance and could be validated in multiple independent external LUAD cohorts. These three genes were differentially expressed in LUAD and lung normal tissues, and might be potential prognostic markers for LUAD.
    CONCLUSION: LUAD can be classified into four different characteristic metabolic subtypes based on the glycolysis- and glutaminolysis-related genes. Nine genes (CXCL8, CNR1, AGER, ALB, S100A7, SLC2A1, TH, SPP1, LEP) may play an important role in the subtype-intrinsic drive. This metabolic subtype classification, provides new biological insights into the previously established LUAD subtypes.
    Keywords:  Glutaminolysis; Glycolysis; Lung adenocarcinoma (LUAD); Metabolic subtype
    DOI:  https://doi.org/10.1186/s12885-023-10622-x
  14. Front Immunol. 2023 ;14 1083069
    Metabolic rearrangements and intratumoral heterogeneity for immune response in hepatocellular carcinoma.
    Fei-Qi Xu, Meng-Meng Dong, Zhi-Fei Wang, Li-Dong Cao.
      Liver cancer is one of the most common malignant tumors globally. Not only is it difficult to diagnose, but treatments are scarce and the prognosis is generally poor. Hepatocellular carcinoma (HCC) is the most common type of liver cancer. Aggressive cancer cells, such as those found in HCC, undergo extensive metabolic rewiring as tumorigenesis, the unique feature, ultimately causes adaptation to the neoplastic microenvironment. Intratumoral heterogeneity (ITH) is defined as the presence of distinct genetic features and different phenotypes in the same tumoral region. ITH, a property unique to malignant cancers, results in differences in many different features of tumors, including, but not limited to, tumor growth and resistance to chemotherapy, which in turn is partly responsible for metabolic reprogramming. Moreover, the different metabolic phenotypes might also activate the immune response to varying degrees and help tumor cells escape detection by the immune system. In this review, we summarize the reprogramming of glucose metabolism and tumoral heterogeneity and their associations that occur in HCC, to obtain a better understanding of the mechanisms of HCC oncogenesis.
    Keywords:  hepatocellular carcinoma; immune response; intratumoral heterogeneity; metabolic rearrangements; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2023.1083069
  15. bioRxiv. 2023 Feb 11. pii: 2023.02.10.524960. [Epub ahead of print]
    Glutathione supports lipid abundance in vivo.
    Gloria Asantewaa, Emily T Tuttle, Nathan P Ward, Yun Pyo Kang, Yumi Kim, Madeline E Kavanagh, Nomeda Girnius, Ying Chen, Renae Duncan, Katherine Rodriguez, Fabio Hecht, Marco Zocchi, Leonid Smorodintsev-Schiller, TashJaé Q Scales, Kira Taylor, Fatemeh Alimohammadi, Zachary R Sechrist, Diana Agostini-Vulaj, Xenia L Schafer, Hayley Chang, Zachary Smith, Thomas N O'Connor, Sarah Whelan, Laura M Selfors, Jett Crowdis, G Kenneth Gray, Roderick T Bronson, Dirk Brenner, Alessandro Rufini, Robert T Dirksen, Aram F Hezel, Aaron R Huber, Josh Munger, Benjamin F Cravatt, Vasilis Vasiliou, Calvin L Cole, Gina M DeNicola, Isaac S Harris.
      Cells rely on antioxidants to survive. The most abundant antioxidant is glutathione (GSH). The synthesis of GSH is non-redundantly controlled by the glutamate-cysteine ligase catalytic subunit (GCLC). GSH imbalance is implicated in many diseases, but the requirement for GSH in adult tissues is unclear. To interrogate this, we developed a series of in vivo models to induce Gclc deletion in adult animals. We find that GSH is essential to lipid abundance in vivo . GSH levels are reported to be highest in liver tissue, which is also a hub for lipid production. While the loss of GSH did not cause liver failure, it decreased lipogenic enzyme expression, circulating triglyceride levels, and fat stores. Mechanistically, we found that GSH promotes lipid abundance by repressing NRF2, a transcription factor induced by oxidative stress. These studies identify GSH as a fulcrum in the liver's balance of redox buffering and triglyceride production.
    DOI:  https://doi.org/10.1101/2023.02.10.524960
This page is being maintained by Thomas Krichel. It was last updated on 2024‒11‒22 at 4:16.