bims-glucam 2023-09-10 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2023–09–10
twelve papers selected by
Sreeparna Banerjee, Middle East Technical University

Metabolic barriers in non-small cell lung cancer with LKB1 and/or KEAP1 mutations for immunotherapeutic strategies.
Genome-scale modeling predicts metabolic differences between macrophage subtypes in colorectal cancer.
Integrative analysis reveals that SLC38A1 promotes hepatocellular carcinoma development via PI3K/AKT/mTOR signaling via glutamine mediated energy metabolism.
Glutaminase (GLS1) gene expression in primary breast cancer.
Metabolic Alterations in Canine Mammary Tumors.
Ootheca mantidis mitigates renal fibrosis in mice by the suppression of apoptosis via increasing the gut microbe Akkermansia muciniphila and modulating glutamine metabolism.
Metabolic reprogramming of three major nutrients in platinum-resistant ovarian cancer.
Intratumoral metabolic heterogeneity of colorectal cancer.
Reconstructing hepatic metabolic profile and glutathione-mediated metabolic fate of acrylamide.
Genomics and transcriptomic alterations of the glutamate receptors in acute myeloid leukemia.
Immunometabolic actions of trabectedin and lurbinectedin on human macrophages: relevance for their anti-tumor activity.
Integrating glycolysis, citric acid cycle, pentose phosphate pathway, and fatty acid beta-oxidation into a single computational model.

Front Oncol. 2023 ;13 1249237

Metabolic barriers in non-small cell lung cancer with LKB1 and/or KEAP1 mutations for immunotherapeutic strategies.

Ichidai Tanaka, Junji Koyama, Hideyuki Itoigawa, Shunsaku Hayai, Masahiro Morise.

  Currently, immune checkpoint inhibitors (ICIs) are widely considered the standard initial treatment for advanced non-small cell lung cancer (NSCLC) when there are no targetable driver oncogenic alternations. NSCLC tumors that have two alterations in tumor suppressor genes, such as liver kinase B1 (LKB1) and/or Kelch-like ECH-associated protein 1 (KEAP1), have been found to exhibit reduced responsiveness to these therapeutic strategies, as revealed by multiomics analyses identifying immunosuppressed phenotypes. Recent advancements in various biological approaches have gradually unveiled the molecular mechanisms underlying intrinsic reprogrammed metabolism in tumor cells, which contribute to the evasion of immune responses by the tumor. Notably, metabolic alterations in glycolysis and glutaminolysis have a significant impact on tumor aggressiveness and the remodeling of the tumor microenvironment. Since glucose and glutamine are essential for the proliferation and activation of effector T cells, heightened consumption of these nutrients by tumor cells results in immunosuppression and resistance to ICI therapies. This review provides a comprehensive summary of the clinical efficacies of current therapeutic strategies against NSCLC harboring LKB1 and/or KEAP1 mutations, along with the metabolic alterations in glycolysis and glutaminolysis observed in these cancer cells. Furthermore, ongoing trials targeting these metabolic alterations are discussed as potential approaches to overcome the extremely poor prognosis associated with this type of cancer.

Keywords:  KEAP1; LKB1; NSCLC; PD-1/PD-L1 inhibitors; glutaminolysis; glycolysis; immune checkpoint blockade; metabolic barriers

DOI:  https://doi.org/10.3389/fonc.2023.1249237
iScience. 2023 Sep 15. 26(9): 107569

Genome-scale modeling predicts metabolic differences between macrophage subtypes in colorectal cancer.

Patrick E Gelbach, Stacey D Finley.

  Colorectal cancer (CRC) shows high incidence and mortality, partly due to the tumor microenvironment (TME), which is viewed as an active promoter of disease progression. Macrophages are among the most abundant cells in the TME. These immune cells are generally categorized as M1, with inflammatory and anti-cancer properties, or M2, which promote tumor proliferation and survival. Although the M1/M2 subclassification scheme is strongly influenced by metabolism, the metabolic divergence between the subtypes remains poorly understood. Therefore, we generated a suite of computational models that characterize the M1- and M2-specific metabolic states. Our models show key differences between the M1 and M2 metabolic networks and capabilities. We leverage the models to identify metabolic perturbations that cause the metabolic state of M2 macrophages to more closely resemble M1 cells. Overall, this work increases understanding of macrophage metabolism in CRC and elucidates strategies to promote the metabolic state of anti-tumor macrophages.

Keywords:  Cancer; Health informatics; Human genetics; Quantitative genetics

DOI:  https://doi.org/10.1016/j.isci.2023.107569
J Cancer Res Clin Oncol. 2023 Sep 06.

Integrative analysis reveals that SLC38A1 promotes hepatocellular carcinoma development via PI3K/AKT/mTOR signaling via glutamine mediated energy metabolism.

Hua-Guo Feng, Chuan-Xin Wu, Guo-Chao Zhong, Jian-Ping Gong, Chun-Mu Miao, Bin Xiong.

  Although hepatocellular carcinoma (HCC) is rather frequent, little is known about the molecular pathways underlying its development, progression, and prognosis. In the current study, we comprehensively analyzed the deferentially expressed metabolism-related genes (MRGs) in HCC based on TCGA datasets attempting to discover the potentially prognostic genes in HCC. The up-regulated MRGs were further subjected to analyze their prognostic values and protein expressions. Twenty-seven genes were identified because their high expressions were significant in OS, PFS, DFS, DSS, and HCC tumor samples. They were then used for GO, KEGG, methylation, genetics changes, immune infiltration analyses. Moreover, we established a prognostic model in HCC using univariate assays and LASSO regression based on these MRGs. Additionally, we also found that SLC38A1, an amino acid metabolism closely related transporter, was a potential prognostic gene in HCC, and its function in HCC was further studied using experiments. We found that the knockdown of SLC38A1 notably suppressed the growth and migration of HCC cells. Further studies revealed that SLC38A1 modulated the development of HCC cells by regulating PI3K/AKT/mTOR signaling via glutamine mediated energy metabolism. In conclusion, this study identified the potentially prognostic MRGs in HCC and uncovered that SLC38A1 regulated HCC development and progression by regulating PI3K/AKT/mTOR signaling via glutamine mediated energy metabolism, which might provide a novel marker and potential therapeutic target in HCC.

Keywords:  Biomarker; Glutamine; Hepatocellular carcinoma; Metabolism‐related genes; PI3K/AKT/mTOR signaling; SLC38A1

DOI:  https://doi.org/10.1007/s00432-023-05360-3
Breast Cancer. 2023 Sep 07.

Glutaminase (GLS1) gene expression in primary breast cancer.

Neelima Vidula, Christina Yau, Hope S Rugo.

   BACKGROUND: Tumor growth is mediated in part by glutamine, and glutaminase is an enzyme necessary for glutamine catabolism. We studied glutaminase (GLS1) gene expression in primary breast cancer to determine correlations with clinical and tumor characteristics, and gene associations in publicly available databases. A better understanding of glutaminase gene expression may help guide further exploration of glutaminase inhibitors in breast cancer.
METHODS: GLS1 mRNA levels were evaluated in The Cancer Genome Atlas (n = 817) and METABRIC (n = 1992) datasets. Associations between GLS1 and tumor subtype (ANOVA followed by post-hoc Tukey test for pairwise comparisons) and selected genes involved in the pathogenesis of breast cancer (Pearson's correlations) were determined in both datasets. In METABRIC, associations with overall survival (Cox proportional hazard model) were determined. For all analyses, p < 0.05 was the threshold for statistical significance.
RESULTS: GLS1 expression was significantly higher in triple negative breast cancer (TNBC) than hormone receptor (HR) +/HER2- and HER2+ breast cancer (p < 0.001) and basal versus luminal A, luminal B, and HER2 enriched breast cancer (p < 0.001) in both datasets. In METABRIC, higher GLS1 expression was associated with improved overall survival (HR 0.91, 95% CI: 0.85-0.97, p = 0.005) and this association remained significant in the TNBC subset (HR 0.83, 95% CI: 0.71-0.98, p = 0.032). GLS1 had significant positive gene correlations with immune, proliferative, and basal genes, and inverse correlations with luminal genes and genes involved in metabolism.
CONCLUSION: GLS1 expression is highest in TNBC and basal breast cancer, supporting ongoing clinical investigation of GLS1 inhibition in TNBC. GLS1 may have prognostic implications but further research is needed to validate this finding. GLS1 had significant positive gene correlations with immune genes, which may have implications for potential combinations of glutaminase inhibition and immunotherapy.

Keywords:  Breast cancer; Gene expression; Glutaminase; METABRIC; TCGA

DOI:  https://doi.org/10.1007/s12282-023-01502-0
Animals (Basel). 2023 Aug 30. pii: 2757. [Epub ahead of print]13(17):

Metabolic Alterations in Canine Mammary Tumors.

Guilherme Henrique Tamarindo, Adriana Alonso Novais, Luiz Gustavo Almeida Chuffa, Debora Aparecida Pires Campos Zuccari.

  Canine mammary tumors (CMTs) are among the most common diseases in female dogs and share similarities with human breast cancer, which makes these animals a model for comparative oncology studies. In these tumors, metabolic reprogramming is known as a hallmark of carcinogenesis whereby cells undergo adjustments to meet the high bioenergetic and biosynthetic demands of rapidly proliferating cells. However, such alterations are also vulnerabilities that may serve as a therapeutic strategy, which has mostly been tested in human clinical trials but is poorly explored in CMTs. In this dedicated review, we compiled the metabolic changes described for CMTs, emphasizing the metabolism of carbohydrates, amino acids, lipids, and mitochondrial functions. We observed key factors associated with the presence and aggressiveness of CMTs, such as an increase in glucose uptake followed by enhanced anaerobic glycolysis via the upregulation of glycolytic enzymes, changes in glutamine catabolism due to the overexpression of glutaminases, increased fatty acid oxidation, and distinct effects depending on lipid saturation, in addition to mitochondrial DNA, which is a hotspot for mutations. Therefore, more attention should be paid to this topic given that targeting metabolic fragilities could improve the outcome of CMTs.

Keywords:  amino acids; cancer; canine mammary tumors; glucose; lipids; metabolic reprogramming; metabolism; mitochondria

DOI:  https://doi.org/10.3390/ani13172757
Biomed Pharmacother. 2023 Sep 05. pii: S0753-3322(23)01232-5. [Epub ahead of print]166 115434

Ootheca mantidis mitigates renal fibrosis in mice by the suppression of apoptosis via increasing the gut microbe Akkermansia muciniphila and modulating glutamine metabolism.

Jue Wang, Xiaozhen Guo, Ziyuan Zou, Minjun Yu, Xueling Li, Hualing Xu, Yiping Chen, Tingying Jiao, Kanglong Wang, Yuandi Ma, Jie Jiang, Xinyu Liang, Jiawen Wang, Cen Xie, Yifei Zhong.

  Renal interstitial fibrosis (RIF), a progressive process affecting the kidneys in chronic kidney disease (CKD), currently lacks an effective therapeutic intervention. Traditional Chinese medicine (TCM) has shown promise in reducing RIF and slowing CKD progression. In this study, we demonstrated the dose-dependent attenuation of RIF by Ootheca mantidis (SPX), a commonly prescribed TCM for CKD, in a mouse model of unilateral ureteral obstruction (UUO). RNA-sequencing analysis suggested that SPX treatment prominently downregulated apoptosis and inflammation-associated pathways, thereby inhibiting the fibrogenic signaling in the kidney. We further found that transplantation of fecal microbiota from SPX-treated mice conferred protection against renal injury and fibrosis through suppressing apoptosis in UUO mice, indicating that SPX ameliorated RIF via remodeling the gut microbiota and reducing apoptosis in the kidneys. Further functional exploration of the gut microbiota combined with fecal metabolomics revealed increased levels of some probiotics, including Akkermansia muciniphila (A. muciniphila), and modulations in glutamine-related amino acid metabolism in UUO mice treated with SPX. Subsequent colonization of A. muciniphila and supplementation with glutamine effectively mitigated cell apoptosis and RIF in UUO mice. Collectively, these findings unveil a functionally A. muciniphila- and glutamine-involved gut-renal axis that contributes to the action of SPX, and provide important clue for the therapeutic potential of SPX, A. muciniphila, and glutamine in combatting RIF.

Keywords:  Akkermansia muciniphila; Apoptosis; Glutamine; Ootheca mantidis; Renal interstitial fibrosis; Unilateral ureteral obstruction

DOI:  https://doi.org/10.1016/j.biopha.2023.115434
Front Oncol. 2023 ;13 1231460

Metabolic reprogramming of three major nutrients in platinum-resistant ovarian cancer.

Jinbowen Yan, Fangzhi Xu, Dan Zhou, Shuo Zhang, Bo Zhang, Qingwei Meng, Qiubo Lv.

  Metabolic reprogramming is a phenomenon in which cancer cells alter their metabolic pathways to support their uncontrolled growth and survival. Platinum-based chemotherapy resistance is associated with changes in glucose metabolism, amino acid metabolism, fatty acid metabolism, and tricarboxylic acid cycle. These changes lead to the creation of metabolic intermediates that can provide precursors for the biosynthesis of cellular components and help maintain cellular energy homeostasis. This article reviews the research progress of the metabolic reprogramming mechanism of platinumbased chemotherapy resistance caused by three major nutrients in ovarian cancer.

Keywords:  amino acid metabolism; glucose metabolism; lipid metabolism; metabolic reprogramming; ovarian cancer; platinum resistance

DOI:  https://doi.org/10.3389/fonc.2023.1231460
Am J Physiol Cell Physiol. 2023 Sep 04.

Intratumoral metabolic heterogeneity of colorectal cancer.

Yoshinobu Hirose, Kohei Taniguchi.

  Although the metabolic phenotype within tumors is known to differ significantly from that of the surrounding normal tissue, the importance of this heterogeneity is just becoming widely recognized. Colorectal cancer (CRC) is often classified as the Warburg phenotype, a metabolic type in which the glycolytic system is predominant over oxidative phosphorylation (OXPHOS) in mitochondria for energy production. However, this dichotomy (glycolysis vs OXPHOS) may be too simplistic and not accurately represent the metabolic characteristics of CRC. Therefore, in this review, we decompose metabolic phenomena into factors based on their source/origin and reclassify them into two categories: extrinsic and intrinsic. In the CRC context, extrinsic factors include those based on the environment, such as hypoxia, nutrient deprivation, and the tumor microenvironment, whereas intrinsic factors include those based on subpopulations, such as pathological subtypes and cancer stem cells. These factors form multiple layers inside and outside the tumor, affecting them additively, dominantly, or mutually exclusively. Consequently, the metabolic phenotype is a heterogeneous and fluid phenomenon reflecting the spatial distribution and temporal continuity of these factors. This allowed us to redefine the characteristics of specific metabolism-related factors in CRC and summarize and update our accumulated knowledge on their heterogeneity. Furthermore, we positioned tumor budding in CRC as an intrinsic factor and a novel form of metabolic heterogeneity, and predicted its metabolic dynamics, noting its similarity to circulating tumor cells and epithelial-mesenchymal transition. Finally, the possibilities and limitations of using human tumor tissue as research material to investigate and assess metabolic heterogeneity are discussed.

Keywords:  colorectal cancer; extrinsic factor; intrinsic factor; metabolic heterogeneity; multilayered model

DOI:  https://doi.org/10.1152/ajpcell.00139.2021
Environ Pollut. 2023 Sep 04. pii: S0269-7491(23)01510-5. [Epub ahead of print] 122508

Reconstructing hepatic metabolic profile and glutathione-mediated metabolic fate of acrylamide.

Yong Wu, Yaoran Li, Wei Jia, Li Zhu, Xuzhi Wan, Sunan Gao, Yu Zhang.

  The toxicity of acrylamide (AA) has continuously attracted wide concerns as its extensive presence from both environmental and dietary sources. However, its hepatic metabolic transformation and metabolic fate still remain unclear. This study aims to unravel the metabolic profile and glutathione (GSH) mediated metabolic fate of AA in liver of rats under the dose-dependent exposure. We found that exposure to AA dose-dependently alters the binding of AA and GSH and the generation of mercapturic acid adducts, while liver as a target tissue bears the metabolic transformation of AA via regulating GSH synthesis and consumption pathways, in which glutamine synthase (GSS), cytochrome P450 2E1 (CYP2E1), and glutathione S-transferase P1 (GSTP1) play a key role. In response to high- and low-dose exposures to AA, there were significant differences in liver of rats, including the changes in GSH and cysteine (CYS) activities, and the conversion ratio of AA to glycidamide (GA), and liver can affect the transformation of AA by regulating the GSH-mediated metabolic pathway. Low-dose exposure to AA activates GSH synthesis pathway in liver and upregulates GSS activity and CYS content with no change in GGT1 activity. High-dose exposure to AA activates the detoxification pathway of GSH and increases GSH consumption by upregulating GSTP1 activity. In addition, molecular docking results showed that most of the metabolic molecules transformed by AA and GA other than themselves can closely bind to GSTP1, glutamine synthase, γ-glutamyl transpeptidase 1, N-acetyltransferase, and dimethyl sulfide dehydrogenase 1. The binding of AA-GSH and GA-GSH to GSTP1 and CYP2E1 enzymes determine the tendentiousness between toxicity and detoxification of AA, which exerts a prospective avenue for targeting protective role of hepatic enzymes against in vivo toxicity of AA.

Keywords:  Acrylamide; Glutathione; Glycidamide; Metabolic fate; Molecular docking

DOI:  https://doi.org/10.1016/j.envpol.2023.122508
Clin Transl Sci. 2023 Sep 05.

Genomics and transcriptomic alterations of the glutamate receptors in acute myeloid leukemia.

Amani Alqahtani, Mengxi Wang, Mimi Lou, Houda Alachkar.

Glutamine and glutamate have been widely explored as potential therapeutic targets in acute myeloid leukemia (AML). In addition to its bioenergetic role in leukemia cell proliferation, L-glutamate is a neurotransmitter that acts on glutamate receptors. However, the role of glutamate receptors in AML is largely understudied. Here, we comprehensively analyze the genomic and transcriptomic alterations of glutamate receptor genes in AML using publicly available data. We investigated the frequency of mutations in the glutamate receptor genes and whether an association exist between the presence of these mutations and clinical and molecular characteristics or patient's clinical outcome. We also assessed the dysregulation of glutamate receptor gene expression in AML with and without mutations and whether gene dysregulation is associated with clinical outcomes. We found that 29 (14.5%) of 200 patients with AML had a mutation in at least one glutamate receptor gene. The DNMT3A mutations were significantly more frequent in patients with mutations in at least one glutamate receptor gene compared with patients without mutations (13 of 29 [44.8%] vs. 41 of 171 [23.9%], p value: 0.02). Notably, patients with mutations in at least one glutamate receptor gene survived shorter than patients without mutations; however, the results did not reach statistical significance (overall survival: 15.5 vs. 19.0 months; p value: 0.10). Mutations in the glutamate receptor genes were not associated with changes in gene expression and the transcriptomic levels of glutamate receptor genes were not associated with clinical outcome.

DOI: https://doi.org/10.1111/cts.13588
Front Immunol. 2023 ;14 1211068

Immunometabolic actions of trabectedin and lurbinectedin on human macrophages: relevance for their anti-tumor activity.

Adrián Povo-Retana, Marco Fariñas, Rodrigo Landauro-Vera, Marina Mojena, Carlota Alvarez-Lucena, Miguel A Fernández-Moreno, Antonio Castrillo, Juan Vladimir de la Rosa Medina, Sergio Sánchez-García, Carles Foguet, Francesc Mas, Silvia Marin, Marta Cascante, Lisardo Boscá.

  In recent years, the central role of cell bioenergetics in regulating immune cell function and fate has been recognized, giving rise to the interest in immunometabolism, an area of research focused on the interaction between metabolic regulation and immune function. Thus, early metabolic changes associated with the polarization of macrophages into pro-inflammatory or pro-resolving cells under different stimuli have been characterized. Tumor-associated macrophages are among the most abundant cells in the tumor microenvironment; however, it exists an unmet need to study the effect of chemotherapeutics on macrophage immunometabolism. Here, we use a systems biology approach that integrates transcriptomics and metabolomics to unveil the immunometabolic effects of trabectedin (TRB) and lurbinectedin (LUR), two DNA-binding agents with proven antitumor activity. Our results show that TRB and LUR activate human macrophages toward a pro-inflammatory phenotype by inducing a specific metabolic rewiring program that includes ROS production, changes in the mitochondrial inner membrane potential, increased pentose phosphate pathway, lactate release, tricarboxylic acids (TCA) cycle, serine and methylglyoxal pathways in human macrophages. Glutamine, aspartate, histidine, and proline intracellular levels are also decreased, whereas oxygen consumption is reduced. The observed immunometabolic changes explain additional antitumor activities of these compounds and open new avenues to design therapeutic interventions that specifically target the immunometabolic landscape in the treatment of cancer.

Keywords:  ROS; immunometabolism; lurbinectedin; macrophages; trabectedin

DOI:  https://doi.org/10.3389/fimmu.2023.1211068
Sci Rep. 2023 09 02. 13(1): 14484

Integrating glycolysis, citric acid cycle, pentose phosphate pathway, and fatty acid beta-oxidation into a single computational model.

Sylwester M Kloska, Krzysztof Pałczyński, Tomasz Marciniak, Tomasz Talaśka, Beata J Wysocki, Paul Davis, Tadeusz A Wysoki.

The metabolic network of a living cell is highly intricate and involves complex interactions between various pathways. In this study, we propose a computational model that integrates glycolysis, the pentose phosphate pathway (PPP), the fatty acids beta-oxidation, and the tricarboxylic acid cycle (TCA cycle) using queueing theory. The model utilizes literature data on metabolite concentrations and enzyme kinetic constants to calculate the probabilities of individual reactions occurring on a microscopic scale, which can be viewed as the reaction rates on a macroscopic scale. However, it should be noted that the model has some limitations, including not accounting for all the reactions in which the metabolites are involved. Therefore, a genetic algorithm (GA) was used to estimate the impact of these external processes. Despite these limitations, our model achieved high accuracy and stability, providing real-time observation of changes in metabolite concentrations. This type of model can help in better understanding the mechanisms of biochemical reactions in cells, which can ultimately contribute to the prevention and treatment of aging, cancer, metabolic diseases, and neurodegenerative disorders.

DOI: https://doi.org/10.1038/s41598-023-41765-3