bims-glucam 2023-04-02 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2023–04–02
23 papers selected by
Sreeparna Banerjee, Middle East Technical University

Glutamine Starvation Affects Cell Cycle, Oxidative Homeostasis and Metabolism in Colorectal Cancer Cells.
A Five Glutamine-Associated Signature Predicts Prognosis of Prostate Cancer and Links Glutamine Metabolism with Tumor Microenvironment.
Amino acid metabolic reprogramming in tumor metastatic colonization.
Metabolic Reprogramming and Potential Therapeutic Targets in Lymphoma.
L-asparaginase anti-tumor activity in pancreatic cancer is dependent on its glutaminase activity and resistance is mediated by glutamine synthetase.
A Toolbox For Glutamine Use In Dissolution Dynamic Nuclear Polarization: From Enzymatic Reaction Monitoring To The Study Of Cellular Metabolic Pathways And Imaging.
Glutamine metabolism-related genes predict prognosis and reshape tumor microenvironment immune characteristics in diffuse gliomas.
Metabolic reprogramming in cancer: Mechanisms and therapeutics.
Nucleotide metabolism: a pan-cancer metabolic dependency.
Constructing interactive networks of functional genes and metabolites to uncover the cellular events related to colorectal cancer cell migration induced by arsenite.
FASN-deficiency induces a cytosol-to-mitochondria citrate flux to mitigate detachment-induced oxidative stress.
Oridonin inhibits Hela cell proliferation via downregulation of glutathione metabolism: a new insight from metabolomics.
Metabolic codependencies in the tumor microenvironment and gastric cancer: Difficulties and opportunities.
Small molecule inhibitors for cancer metabolism: promising prospects to be explored.
Ensemble-based genome-scale modeling predicts metabolic differences between macrophage subtypes in colorectal cancer.
MiRNAs Action and Impact on Mitochondria Function, Metabolic Reprogramming and Chemoresistance of Cancer Cells: A Systematic Review.
HDAC4-mediated deacetylation of glutaminase facilitates glioma stemness.
Cellular Red-Ox system in health and disease: The latest update.
Identification and Characterization of Metabolic Subtypes of Endometrial Cancer Using a Systems-Level Approach.
Targeting glutaminase 1 (GLS1) by small molecules for anticancer therapeutics.
Functional comparison of metabolic networks across species.
Molecular Basis of the KEAP1-NRF2 Signaling Pathway.
The construction and analysis of tricarboxylic acid cycle related prognostic model for cervical cancer.

Antioxidants (Basel). 2023 Mar 10. pii: 683. [Epub ahead of print]12(3):

Glutamine Starvation Affects Cell Cycle, Oxidative Homeostasis and Metabolism in Colorectal Cancer Cells.

Martina Spada, Cristina Piras, Giulia Diana, Vera Piera Leoni, Daniela Virginia Frau, Gabriele Serreli, Gabriella Simbula, Roberto Loi, Antonio Noto, Federica Murgia, Paola Caria, Luigi Atzori.

  Cancer cells adjust their metabolism to meet energy demands. In particular, glutamine addiction represents a distinctive feature of several types of tumors, including colorectal cancer. In this study, four colorectal cancer cell lines (Caco-2, HCT116, HT29 and SW480) were cultured with or without glutamine. The growth and proliferation rate, colony-forming capacity, apoptosis, cell cycle, redox homeostasis and metabolomic analysis were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test (MTT), flow cytometry, high-performance liquid chromatography and gas chromatography/mass spectrometry techniques. The results show that glutamine represents an important metabolite for cell growth and that its deprivation reduces the proliferation of colorectal cancer cells. Glutamine depletion induces cell death and cell cycle arrest in the GO/G1 phase by modulating energy metabolism, the amino acid content and antioxidant defenses. Moreover, the combined glutamine starvation with the glycolysis inhibitor 2-deoxy-D-glucose exerted a stronger cytotoxic effect. This study offers a strong rationale for targeting glutamine metabolism alone or in combination with glucose metabolism to achieve a therapeutic benefit in the treatment of colon cancer.

Keywords:  antioxidant defenses; cancer cell metabolism; colorectal cancer; energetic pathways; glutamine starvation; metabolomics

DOI:  https://doi.org/10.3390/antiox12030683
J Clin Med. 2023 Mar 14. pii: 2243. [Epub ahead of print]12(6):

A Five Glutamine-Associated Signature Predicts Prognosis of Prostate Cancer and Links Glutamine Metabolism with Tumor Microenvironment.

Hai Wang, Yuxiao Chen, Wei Zhao, Haolin Liu, Hongtao Tu, Zhongyou Xia, Rui Wang, Jinze Tang, Chuang Zhu, Rui Li, Xiaodong Liu, Peng Gu.

  Glutamine has been recognized as an important amino acid that provide a variety of intermediate products to fuel biosynthesis. Glutamine metabolism participates in the progression of the tumor via various mechanisms. However, glutamine-metabolism-associated signatures and its significance in prostate cancer are still unclear. In this current study, we identified five genes associated with glutamine metabolism by univariate and Lasso regression analysis and constructed a model to predict the biochemical recurrence free survival (BCRFS) of PCa. Further validation of the prognostic risk model demonstrated a good efficacy in predicting the BCRFS in PCa patients. Interestingly, based on the CIBERSORTx, ssGSEA and ESTIMATE algorithms predictions, we noticed a distinct immune cell infiltration and immune pathway pattern in the prediction of the two risk groups stratified by the risk model. Drug sensitivity prediction revealed that patients in the high-risk group were more suitable for chemotherapy. Last but not least, glutamine deprivation significantly inhibited cell growth in GLUL or ASNS knock down prostate cancer cell lines. Therefore, we proposed a novel prognostic model by using glutamine metabolism genes for PCa patients and identified potential mechanism of PCa progression through glutamine-related tumor microenvironment remodeling.

Keywords:  biochemical recurrence; glutamine; prediction model; prostate cancer; tumor microenvironment

DOI:  https://doi.org/10.3390/jcm12062243
Front Oncol. 2023 ;13 1123192

Amino acid metabolic reprogramming in tumor metastatic colonization.

Zihao Wang, Xingyun Wu, Hai-Ning Chen, Kui Wang.

  Metastasis is considered as the major cause of cancer death. Cancer cells can be released from primary tumors into the circulation and then colonize in distant organs. How cancer cells acquire the ability to colonize in distant organs has always been the focus of tumor biology. To enable survival and growth in the new environment, metastases commonly reprogram their metabolic states and therefore display different metabolic properties and preferences compared with the primary lesions. For different microenvironments in various colonization sites, cancer cells must transfer to specific metabolic states to colonize in different distant organs, which provides the possibility of evaluating metastasis tendency by tumor metabolic states. Amino acids provide crucial precursors for many biosynthesis and play an essential role in cancer metastasis. Evidence has proved the hyperactivation of several amino acid biosynthetic pathways in metastatic cancer cells, including glutamine, serine, glycine, branched chain amino acids (BCAAs), proline, and asparagine metabolism. The reprogramming of amino acid metabolism can orchestrate energy supply, redox homeostasis, and other metabolism-associated pathways during cancer metastasis. Here, we review the role and function of amino acid metabolic reprogramming in cancer cells colonizing in common metastatic organs, including lung, liver, brain, peritoneum, and bone. In addition, we summarize the current biomarker identification and drug development of cancer metastasis under the amino acid metabolism reprogramming, and discuss the possibility and prospect of targeting organ-specific metastasis for cancer treatment.

Keywords:  amino acid metabolism; cancer metastasis; distant organ colonization; metabolic reprogramming; metabolic targeting

DOI:  https://doi.org/10.3389/fonc.2023.1123192
Int J Mol Sci. 2023 Mar 13. pii: 5493. [Epub ahead of print]24(6):

Metabolic Reprogramming and Potential Therapeutic Targets in Lymphoma.

Yuyang Pang, Tingxun Lu, Zijun Y Xu-Monette, Ken H Young.

  Lymphoma is a heterogeneous group of diseases that often require their metabolism program to fulfill the demand of cell proliferation. Features of metabolism in lymphoma cells include high glucose uptake, deregulated expression of enzymes related to glycolysis, dual capacity for glycolytic and oxidative metabolism, elevated glutamine metabolism, and fatty acid synthesis. These aberrant metabolic changes lead to tumorigenesis, disease progression, and resistance to lymphoma chemotherapy. This metabolic reprogramming, including glucose, nucleic acid, fatty acid, and amino acid metabolism, is a dynamic process caused not only by genetic and epigenetic changes, but also by changes in the microenvironment affected by viral infections. Notably, some critical metabolic enzymes and metabolites may play vital roles in lymphomagenesis and progression. Recent studies have uncovered that metabolic pathways might have clinical impacts on the diagnosis, characterization, and treatment of lymphoma subtypes. However, determining the clinical relevance of biomarkers and therapeutic targets related to lymphoma metabolism is still challenging. In this review, we systematically summarize current studies on metabolism reprogramming in lymphoma, and we mainly focus on disorders of glucose, amino acids, and lipid metabolisms, as well as dysregulation of molecules in metabolic pathways, oncometabolites, and potential metabolic biomarkers. We then discuss strategies directly or indirectly for those potential therapeutic targets. Finally, we prospect the future directions of lymphoma treatment on metabolic reprogramming.

Keywords:  lymphoma; metabolism; targeted therapy

DOI:  https://doi.org/10.3390/ijms24065493
Exp Cell Res. 2023 Mar 24. pii: S0014-4827(23)00115-5. [Epub ahead of print]426(2): 113568

L-asparaginase anti-tumor activity in pancreatic cancer is dependent on its glutaminase activity and resistance is mediated by glutamine synthetase.

Jonathan Blachier, Aurore Cleret, Nathalie Guerin, Clara Gil, Jean-Marc Fanjat, Florian Tavernier, Laura Vidault, Fanny Gallix, Nicolas Rama, Rodrigue Rossignol, Diana Piedrahita, Aurély Andrivon, Marie Châlons-Cottavoz, Karine Aguera, Fabien Gay, Françoise Horand, Bastien Laperrousaz.

  l-Asparaginase is a cornerstone of acute lymphoblastic leukemia (ALL) therapy since lymphoblasts lack asparagine synthetase (ASNS) and rely on extracellular asparagine availability for survival. Resistance mechanisms are associated with increased ASNS expression in ALL. However, the association between ASNS and l-Asparaginase efficacy in solid tumors remains unclear, thus limiting clinical development. Interestingly, l-Asparaginase also has a glutaminase co-activity that is crucial in pancreatic cancer where KRAS mutations activate glutamine metabolism. By developing l-Asparaginase-resistant pancreatic cancer cells and using OMICS approaches, we identified glutamine synthetase (GS) as a marker of resistance to l-Asparaginase. GS is the only enzyme able to synthesize glutamine, and its expression also correlates with l-Asparaginase efficacy in 27 human cell lines from 11 cancer indications. Finally, we further demonstrated that GS inhibition prevents cancer cell adaptation to l-Asparaginase-induced glutamine starvation. These findings could pave the way to the development of promising drug combinations to overcome l-Asparaginase resistance.

Keywords:  Drug resistance; Glutamine; Glutamine synthetase; Pancreatic cancer; l-asparaginase

DOI:  https://doi.org/10.1016/j.yexcr.2023.113568
Chemphyschem. 2023 Mar 27. e202300151

A Toolbox For Glutamine Use In Dissolution Dynamic Nuclear Polarization: From Enzymatic Reaction Monitoring To The Study Of Cellular Metabolic Pathways And Imaging.

Karen Dos Santos, Gildas Bertho, Cédric Caradeuc, Véronique Baud, Aurélie Montagne, Daniel Abergel, Nicolas Giraud, Mathieu Baudin.

  Glutamine is under scrutiny regarding its metabolic deregulation linked to energetic reprogramming in cancer cells. Many analytical techniques have been used to understand better the impact of the metabolism of amino acids on biological processes, however only a few are suited to work with complex samples. Here, we report the use of general dissolution dynamic nuclear polarization (D-DNP) formulation using an unexpensive radical as multipurpose tool to study glutamine, with insights from enzymatic modelling to complex metabolic networks and fast imaging. First, hyperpolarized [5-13C] glutamine is used as molecular probe to study the kinetic action of two enzymes: L-asparaginase that has been used as an anti-metabolic treatment for cancer, and glutaminase. These results are also compared with those acquired with another hyperpolarized amino acid, [1,4-13C] asparagine. Second, we explored the use of hyperpolarized (HP) substrates to probe metabolic pathways by monitoring metabolic profiles arising from hyperpolarized glutamine in E. coli extracts. Finally, a highly concentrated sample formulation is proposed for the purpose of fast imaging applications. We think that this approach can be extended to formulate other amino acids as well as other metabolites and provide complementary insights into the analysis of metabolic networks.

Keywords:  amino acids; dissolution dynamic nuclear polarization; glutamine; magnetic resonance; metabolism

DOI:  https://doi.org/10.1002/cphc.202300151
Front Neurol. 2023 ;14 1104738

Glutamine metabolism-related genes predict prognosis and reshape tumor microenvironment immune characteristics in diffuse gliomas.

Huanhuan Fan, Shuxin Zhang, Yunbo Yuan, Siliang Chen, Wenhao Li, Zhihao Wang, Yufan Xiang, Junhong Li, Xiaohong Ma, Yanhui Liu.

   Background: Diffuse gliomas possess a kind of malignant brain tumor with high mortality. Glutamine represents the most abundant and versatile amino acid in the body. Glutamine not only plays an important role in cell metabolism but also involves in cell survival and malignancies progression. Recent studies indicate that glutamine could also affect the metabolism of immune cells in the tumor microenvironment (TME).
Materials and methods: The transcriptome data and clinicopathological information of patients with glioma were acquired from TCGA, CGGA, and West China Hospital (WCH). The glutamine metabolism-related genes (GMRGs) were retrieved from the Molecular Signature Database. Consensus clustering analysis was used to discover expression patterns of GMRGs, and glutamine metabolism risk scores (GMRSs) were established to model tumor aggressiveness-related GMRG expression signature. ESTIMATE and CIBERSORTx were applied to depict the TME immune landscape. The tumor immunological phenotype analysis and TIDE were utilized for predicting the therapeutic response of immunotherapy.
Results: A total of 106 GMRGs were retrieved. Two distinct clusters were established by consensus clustering analysis, which showed a close association with the IDH mutational status of gliomas. In both IDH-mutant and IDH-wildtype gliomas, cluster 2 had significantly shorter overall survival compared with cluster 1, and the differentially expressed genes between the two clusters enriched in pathways related to malignant transformation as well as immunity. In silico TME analysis of the two IDH subtypes revealed not only significantly different immune cell infiltrations and immune phenotypes between the GMRG expression clusters but also different predicted responses to immunotherapy. After the screening, a total of 10 GMRGs were selected to build the GMRS. Survival analysis demonstrated the independent prognostic role of GMRS. Prognostic nomograms were established to predict 1-, 2-, and 3-year survival rates in the four cohorts.
Conclusion: Different subtypes of glutamine metabolism could affect the aggressiveness and TME immune features of diffuse glioma, despite their IDH mutational status. The expression signature of GMRGs could not only predict the outcome of patients with glioma but also be combined into an accurate prognostic nomogram.

Keywords:  diffuse glioma; glutamine metabolism; immune; prognosis; tumor microenvironment

DOI:  https://doi.org/10.3389/fneur.2023.1104738
MedComm (2020). 2023 Apr;4(2): e218

Metabolic reprogramming in cancer: Mechanisms and therapeutics.

Shiqi Nong, Xiaoyue Han, Yu Xiang, Yuran Qian, Yuhao Wei, Tingyue Zhang, Keyue Tian, Kai Shen, Jing Yang, Xuelei Ma.

  Cancer cells characterized by uncontrolled growth and proliferation require altered metabolic processes to maintain this characteristic. Metabolic reprogramming is a process mediated by various factors, including oncogenes, tumor suppressor genes, changes in growth factors, and tumor-host cell interactions, which help to meet the needs of cancer cell anabolism and promote tumor development. Metabolic reprogramming in tumor cells is dynamically variable, depending on the tumor type and microenvironment, and reprogramming involves multiple metabolic pathways. These metabolic pathways have complex mechanisms and involve the coordination of various signaling molecules, proteins, and enzymes, which increases the resistance of tumor cells to traditional antitumor therapies. With the development of cancer therapies, metabolic reprogramming has been recognized as a new therapeutic target for metabolic changes in tumor cells. Therefore, understanding how multiple metabolic pathways in cancer cells change can provide a reference for the development of new therapies for tumor treatment. Here, we systemically reviewed the metabolic changes and their alteration factors, together with the current tumor regulation treatments and other possible treatments that are still under investigation. Continuous efforts are needed to further explore the mechanism of cancer metabolism reprogramming and corresponding metabolic treatments.

Keywords:  cancer metabolism; cancer therapy; glycolysis; metabolic reprogramming

DOI:  https://doi.org/10.1002/mco2.218
Nat Rev Cancer. 2023 Mar 27.

Nucleotide metabolism: a pan-cancer metabolic dependency.

Nicholas J Mullen, Pankaj K Singh.

Metabolic alterations are a key hallmark of cancer cells, and the augmented synthesis and use of nucleotide triphosphates is a critical and universal metabolic dependency of cancer cells across different cancer types and genetic backgrounds. Many of the aggressive behaviours of cancer cells, including uncontrolled proliferation, chemotherapy resistance, immune evasion and metastasis, rely heavily on augmented nucleotide metabolism. Furthermore, most of the known oncogenic drivers upregulate nucleotide biosynthetic capacity, suggesting that this phenotype is a prerequisite for cancer initiation and progression. Despite the wealth of data demonstrating the efficacy of nucleotide synthesis inhibitors in preclinical cancer models and the well-established clinical use of these drugs in certain cancer settings, the full potential of these agents remains unrealized. In this Review, we discuss recent studies that have generated mechanistic insights into the diverse biological roles of hyperactive cancer cell nucleotide metabolism. We explore opportunities for combination therapies that are highlighted by these recent advances and detail key questions that remain to be answered, with the goal of informing urgently warranted future studies.

DOI: https://doi.org/10.1038/s41568-023-00557-7
Environ Int. 2023 Mar 21. pii: S0160-4120(23)00133-2. [Epub ahead of print]174 107860

Constructing interactive networks of functional genes and metabolites to uncover the cellular events related to colorectal cancer cell migration induced by arsenite.

Ruijia Zhang, Jin Sun, Lanyin Tu, Wenhua Lu, Yizheng Li, Tiangang Luan, Baowei Chen.

  Tumor cell migration induced by arsenite (iAsIII) is closely associated with cancer progression. However, transcriptomic and metabolic traits of migrative human cells exposed to iAsIII remain to be well characterized. Here, the combination of transcriptomics and metabolomics approaches were employed to construct interactive networks of functional genes and metabolites in human colorectal cancer (DLD-1) cells exposed to iAsIII. The number of DLD-1 cells passing through the Transwell membrane was at least 6 times greater in the iAsIII-treated groups than in controls. Following iAsIII treatment, the expression of ZEB1 and SLUG protein was significantly upregulated while the expression of CRB2 was downregulated (p < 0.05), indicating the onset of epithelial to mesenchymal transition (EMT). Meanwhile, integrin- and collagen-mediated biological adhesion were enhanced by SLUG under iAsIII treatment. The expression of matrix metallopeptidase (MMP) genes was fostered by iAsIII, which have the functions to degrade extracellular matrix. Glutamine metabolism could be considerably interfered by iAsIII, and in turn glutamine supplementation could effectively enhance DLD-1 cell movement. Overall, our results suggested that DLD-1 cell migration could be promoted by iAsIII via a series of cellular events, including EMT activation, altered cell adhesion, MMP-dependent matrix degradation, accompanying with a metabolic focus on glutamine.

Keywords:  Arsenite; Cell migration; Epithelial to mesenchymal transition; Extracellular matrix; Glutamine

DOI:  https://doi.org/10.1016/j.envint.2023.107860
bioRxiv. 2023 Mar 15. pii: 2023.03.14.532533. [Epub ahead of print]

FASN-deficiency induces a cytosol-to-mitochondria citrate flux to mitigate detachment-induced oxidative stress.

Wenting Dai, Zhichao Wang, Guan Wang, Qiong A Wang, Ralph DeBerardinis, Lei Jiang.

Fatty acid synthase (FASN) maintains de novo lipogenesis (DNL) to support rapid growth in most proliferating cancer cells. Lipogenic acetyl-CoA is primarily produced from carbohydrates but can arise from glutamine-dependent reductive carboxylation under hypoxia. Here we show that reductive carboxylation also occurs in the absence of DNL in cells with defective FASN. In this state, reductive carboxylation was mainly catalyzed by isocitrate dehydrogenase-1 (IDH1) in the cytosol, but IDH1-generated citrate was not used for DNL. Metabolic flux analysis (MFA) revealed that FASN-deficiency induced a net cytosol-to-mitochondria citrate flux through citrate transport protein (CTP). A similar pathway was previously shown to mitigate detachment-induced mitochondrial reactive oxygen species (mtROS) in anchorage-independent tumor spheroids. We further demonstrate that FASN-deficient cells acquire resistance to oxidative stress in a CTP- and IDH1-dependent manner. Together with the reduced FASN activity in tumor spheroids, these data indicate that anchorage-independent malignant cells trade FASN-supported rapid growth for a cytosol-to-mitochondria citrate flux to gain redox capacity against detachment-induced oxidative stress.

DOI: https://doi.org/10.1101/2023.03.14.532533
J Pharm Pharmacol. 2023 Mar 27. pii: rgad025. [Epub ahead of print]

Oridonin inhibits Hela cell proliferation via downregulation of glutathione metabolism: a new insight from metabolomics.

Weijia Wang, Nan Zhang.

   OBJECTIVES: This study aims to elucidate Oridonin' s inhibitory mechanism to cervical cancer using metabolomics methods and pharmacological assays.
METHODS: Network pharmacology and KEGG pathway analysis are used to identify overlapped targets and involved metabolic pathways. UPLC-MS/MS metabolomics analysis is used to determine altered metabolites after Oridonin treatment. Other bioassays are also employed to uncover the changes in critical molecules that are highly related to altered metabolites.
KEY FINDINGS: Seventy-five overlapped targets are identified between Oridonin and cervical cancer. Twenty-one metabolites involved in tricarboxylic acid cycle glutathione metabolism, branched-chain amino acid metabolism and so on changes significantly after Oridonin treatment. Oridonin treatment significantly reduces the content of cysteine and inhibit the catalytic activity of glutamine-cysteine ligase subunit, a rate-limiting enzyme for the synthesis of glutathione. As a result, the content of glutathione is also reduced. The antioxidant enzyme glutathione peroxidase 4 which uses glutathione as a cofactor, is inactivated, resulting in a burst release of reactive oxygen species. The ATP content is also significantly reduced in Hela cells after Oridonin treatment.
CONCLUSIONS: This study finds that Oridonin treatment induces Hela cell apoptosis possibly via inhibition of the glutathione metabolism.

Keywords:  cell apoptosis; cervical cancer; glutathione metabolism; metabolomics; oridonin; reactive oxygen species

DOI:  https://doi.org/10.1093/jpp/rgad025
Biomed Pharmacother. 2023 Mar 27. pii: S0753-3322(23)00389-X. [Epub ahead of print]162 114601

Metabolic codependencies in the tumor microenvironment and gastric cancer: Difficulties and opportunities.

Xihe Zhao, Kai Li, Mengyu Chen, Lei Liu.

  Oncogenesis and the development of tumors affect metabolism throughout the body. Metabolic reprogramming (also known as metabolic remodeling) is a feature of malignant tumors that is driven by oncogenic changes in the cancer cells themselves as well as by cytokines in the tumor microenvironment. These include endothelial cells, matrix fibroblasts, immune cells, and malignant tumor cells. The heterogeneity of mutant clones is affected by the actions of other cells in the tumor and by metabolites and cytokines in the microenvironment. Metabolism can also influence immune cell phenotype and function. Metabolic reprogramming of cancer cells is the result of a convergence of both internal and external signals. The basal metabolic state is maintained by internal signaling, while external signaling fine-tunes the metabolic process based on metabolite availability and cellular needs. This paper reviews the metabolic characteristics of gastric cancer, focusing on the intrinsic and extrinsic mechanisms that drive cancer metabolism in the tumor microenvironment, and interactions between tumor cell metabolic changes and microenvironment metabolic changes. This information will be helpful for the individualized metabolic treatment of gastric cancers.

Keywords:  Codependencies; Gastric cancer; Immunal reprogramming; Metabolism; Microenviroment

DOI:  https://doi.org/10.1016/j.biopha.2023.114601
J Cancer Res Clin Oncol. 2023 Mar 31.

Small molecule inhibitors for cancer metabolism: promising prospects to be explored.

Dan Liu, HongPing Wang, XingXing Li, JiFang Liu, YanLing Zhang, Jing Hu.

   BACKGROUND: Abnormal metabolism is the main hallmark of cancer, and cancer metabolism plays an important role in tumorigenesis, metastasis, and drug resistance. Therefore, studying the changes of tumor metabolic pathways is beneficial to find targets for the treatment of cancer diseases. The success of metabolism-targeted chemotherapy suggests that cancer metabolism research will provide potential new targets for the treatment of malignant tumors.
PURPOSE: The aim of this study was to systemically review recent research findings on targeted inhibitors of tumor metabolism. In addition, we summarized new insights into tumor metabolic reprogramming and discussed how to guide the exploration of new strategies for cancer-targeted therapy.
CONCLUSION: Cancer cells have shown various altered metabolic pathways, providing sufficient fuel for their survival. The combination of these pathways is considered to be a more useful method for screening multilateral pathways. Better understanding of the clinical research progress of small molecule inhibitors of potential targets of tumor metabolism will help to explore more effective cancer treatment strategies.

Keywords:  Cancer metabolism; Drug development; Metabolic reprogramming; Small molecules; Targeted therapy; Tumor microenvironment

DOI:  https://doi.org/10.1007/s00432-022-04501-4
bioRxiv. 2023 Mar 11. pii: 2023.03.09.532000. [Epub ahead of print]

Ensemble-based genome-scale modeling predicts metabolic differences between macrophage subtypes in colorectal cancer.

Patrick E Gelbach, Stacey D Finley.

1Colorectal cancer (CRC) shows high incidence and mortality, partly due to the tumor microenvironment, which is viewed as an active promoter of disease progression. Macrophages are among the most abundant cells in the tumor microenvironment. 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.

DOI: https://doi.org/10.1101/2023.03.09.532000
Biomedicines. 2023 Feb 24. pii: 693. [Epub ahead of print]11(3):

MiRNAs Action and Impact on Mitochondria Function, Metabolic Reprogramming and Chemoresistance of Cancer Cells: A Systematic Review.

Daiane Rosolen, Emanuelle Nunes-Souza, Rafael Marchi, Maria Vitoria Tofolo, Valquíria C Antunes, Fernanda C B Berti, Aline S Fonseca, Luciane R Cavalli.

  MicroRNAs (miRNAs) are involved in the regulation of mitochondrial function and homeostasis, and in the modulation of cell metabolism, by targeting known oncogenes and tumor suppressor genes of metabolic-related signaling pathways involved in the hallmarks of cancer. This systematic review focuses on articles describing the role, association, and/or involvement of miRNAs in regulating the mitochondrial function and metabolic reprogramming of cancer cells. Following the PRISMA guidelines, the articles reviewed were published from January 2010 to September 2022, with the search terms "mitochondrial microRNA" and its synonyms (mitochondrial microRNA, mitochondrial miRNA, mito microRNA, or mitomiR), "reprogramming metabolism," and "cancer" in the title or abstract). Thirty-six original research articles were selected, revealing 51 miRNAs with altered expression in 12 cancers: bladder, breast, cervical, colon, colorectal, liver, lung, melanoma, osteosarcoma, pancreatic, prostate, and tongue. The actions of miRNAs and their corresponding target genes have been reported mainly in cell metabolic processes, mitochondrial dynamics, mitophagy, apoptosis, redox signaling, and resistance to chemotherapeutic agents. Altogether, these studies support the role of miRNAs in the metabolic reprogramming hallmark of cancer cells and highlight their potential as predictive molecular markers of treatment response and/or targets that can be used for therapeutic intervention.

Keywords:  cancer; chemoresistance; metabolic reprogramming; microRNA; mitochondria; mitomiRs

DOI:  https://doi.org/10.3390/biomedicines11030693
Curr Cancer Drug Targets. 2023 Mar 29.

HDAC4-mediated deacetylation of glutaminase facilitates glioma stemness.

Gang Xu, Jianqiang Qu, Ming Zhang.

   BACKGROUND: Inhibiting cancer metabolism via glutaminase (GAC) is a promising strategy to disrupt tumor progression. However, the mechanism regarding GAC acetylation remains largely unknown.
METHODS: Mitochondrial protein isolation and glutaminase activity assay were used to examine GAC activity; RT-qPCR, western blot, sphere-formation, ALDH activity and tumor-initiating assays were performed to evaluate the alteration of cell stemness; Co-IP and rescuing experiments were constructed to explore the underlying mechanisms.
RESULTS: In this study, we demonstrated that GAC acetylation was a vital post-translational modification that inhibits GAC activity in glioma. We identified that GAC was deacetylated by HDAC4, a class II deacetylase. GAC acetylation stimulated the interaction between GAC and SIRT5, therefore promoting GAC ubiquitination and inhibiting GAC activity. Furthermore, GAC overexpression suppressed the stemness of glioma cells, which was rescued by deacetylation of GAC.
CONCLUSION: Our findings reveal a novel mechanism of GAC regulation by acetylation and ubiquitination that participates in glioma stemness.

Keywords:  Acetylation; Cancer metabolism; Glioma; Glutaminase; Stemness

DOI:  https://doi.org/10.2174/1568009623666230329123358
Biomed Pharmacother. 2023 Mar 27. pii: S0753-3322(23)00394-3. [Epub ahead of print]162 114606

Cellular Red-Ox system in health and disease: The latest update.

Atala Bihari Jena, Rashmi Rekha Samal, Nitish Kumar Bhol, Asim K Duttaroy.

  Cells are continually exposed to reactive oxygen species (ROS) generated during cellular metabolism. Apoptosis, necrosis, and autophagy are biological processes involving a feedback cycle that causes ROS molecules to induce oxidative stress. To adapt to ROS exposure, living cells develop various defense mechanisms to neutralize and use ROS as a signaling molecule. The cellular redox networks combine signaling pathways that regulate cell metabolism, energy, cell survival, and cell death. Superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) are essential antioxidant enzymes that are required for scavenging ROS in various cell compartments and response to stressful situations. Among the non-enzymatic defenses, vitamin C, glutathione (GSH), polyphenols, carotenoids, vitamin E, etc., are also essential. This review article describes how ROS are produced as byproducts of oxidation/reduction (redox) processes and how the antioxidants defense system is directly or indirectly engaged in scavenging ROS. In addition, we used computational methods to determine the comparative profile of binding energies of several antioxidants with antioxidant enzymes. The computational analysis demonstrates that antioxidants with a high affinity for antioxidant enzymes regulate their structures.

Keywords:  Antioxidants; CVD; Cancers; Disease; Free radicals; GPx; GSH; ROS; Red-OX

DOI:  https://doi.org/10.1016/j.biopha.2023.114606
Metabolites. 2023 Mar 09. pii: 409. [Epub ahead of print]13(3):

Identification and Characterization of Metabolic Subtypes of Endometrial Cancer Using a Systems-Level Approach.

Akansha Srivastava, Palakkad Krishnanunni Vinod.

  Endometrial cancer (EC) is the most common gynecological cancer worldwide. Understanding metabolic adaptation and its heterogeneity in tumor tissues may provide new insights and help in cancer diagnosis, prognosis, and treatment. In this study, we investigated metabolic alterations of EC to understand the variations in metabolism within tumor samples. Integration of transcriptomics data of EC (RNA-Seq) and the human genome-scale metabolic network was performed to identify the metabolic subtypes of EC and uncover the underlying dysregulated metabolic pathways and reporter metabolites in each subtype. The relationship between metabolic subtypes and clinical variables was explored. Further, we correlated the metabolic changes occurring at the transcriptome level with the genomic alterations. Based on metabolic profile, EC patients were stratified into two subtypes (metabolic subtype-1 and subtype-2) that significantly correlated to patient survival, tumor stages, mutation, and copy number variations. We observed the co-activation of the pentose phosphate pathway, one-carbon metabolism, and genes involved in controlling estrogen levels in metabolic subtype-2, which is linked to poor survival. PNMT and ERBB2 are also upregulated in metabolic subtype-2 samples and present on the same chromosome locus 17q12, which is amplified. PTEN and TP53 mutations show mutually exclusive behavior between subtypes and display a difference in survival. This work identifies metabolic subtypes with distinct characteristics at the transcriptome and genome levels, highlighting the metabolic heterogeneity within EC.

Keywords:  endometrial cancer; metabolic reprogramming; reporter metabolites; systems biology; transcriptome

DOI:  https://doi.org/10.3390/metabo13030409
Eur J Med Chem. 2023 Mar 23. pii: S0223-5234(23)00272-6. [Epub ahead of print]252 115306

Targeting glutaminase 1 (GLS1) by small molecules for anticancer therapeutics.

Yangyang Chen, Lun Tan, Jing Gao, Congcong Lin, Fengbo Wu, Yang Li, Jifa Zhang.

  Glutaminase-1 (GLS1) is a critical enzyme involved in several cellular processes, and its overexpression has been linked to the development and progression of cancer. Based on existing research, GLS1 plays a crucial role in the metabolic activities of cancer cells, promoting rapid proliferation, cell survival, and immune evasion. Therefore, targeting GLS1 has been proposed as a promising cancer therapy strategy, with several GLS1 inhibitors currently under development. To date, several GLS1 inhibitors have been identified, which can be broadly classified into two types: active site and allosteric inhibitors. Despite their pre-clinical effectiveness, only a few number of these inhibitors have advanced to initial clinical trials. Hence, the present medical research emphasizes the need for developing small molecule inhibitors of GLS1 possessing significantly high potency and selectivity. In this manuscript, we aim to summarize the regulatory role of GLS1 in physiological and pathophysiological processes. We also provide a comprehensive overview of the development of GLS1 inhibitors, focusing on multiple aspects such as target selectivity, in vitro and in vivo potency and structure-activity relationships.

Keywords:  Glutaminase-1; Small-molecule inhibitors; Structure-activity relationships (SARs); X-ray co-crystal structure analyses

DOI:  https://doi.org/10.1016/j.ejmech.2023.115306
Nat Commun. 2023 Mar 27. 14(1): 1699

Functional comparison of metabolic networks across species.

Charlotte Ramon, Jörg Stelling.

Metabolic phenotypes are pivotal for many areas, but disentangling how evolutionary history and environmental adaptation shape these phenotypes is an open problem. Especially for microbes, which are metabolically diverse and often interact in complex communities, few phenotypes can be determined directly. Instead, potential phenotypes are commonly inferred from genomic information, and rarely were model-predicted phenotypes employed beyond the species level. Here, we propose sensitivity correlations to quantify similarity of predicted metabolic network responses to perturbations, and thereby link genotype and environment to phenotype. We show that these correlations provide a consistent functional complement to genomic information by capturing how network context shapes gene function. This enables, for example, phylogenetic inference across all domains of life at the organism level. For 245 bacterial species, we identify conserved and variable metabolic functions, elucidate the quantitative impact of evolutionary history and ecological niche on these functions, and generate hypotheses on associated metabolic phenotypes. We expect our framework for the joint interpretation of metabolic phenotypes, evolution, and environment to help guide future empirical studies.

DOI: https://doi.org/10.1038/s41467-023-37429-5
Mol Cells. 2023 Mar 31. 46(3): 133-141

Molecular Basis of the KEAP1-NRF2 Signaling Pathway.

Takafumi Suzuki, Jun Takahashi, Masayuki Yamamoto.

  Transcription factor NRF2 (NF-E2-related factor 2) is a master regulator of cellular responses against environmental stresses. NRF2 induces expression of detoxification and antioxidant enzymes and suppresses inductions of pro-inflammatory cytokine genes. KEAP1 (Kelch-like ECH-associated protein 1) is an adaptor subunit of CULLIN 3 (CUL3)-based E3 ubiquitin ligase. KEAP1 regulates the activity of NRF2 and acts as a sensor for oxidative and electrophilic stresses. NRF2 has been found to be activated in many types of cancers with poor prognosis. Therapeutic strategies to control NRF2-overeactivated cancers have been considered not only by targeting cancer cells with NRF2 inhibitors or NRF2 synthetic lethal chemicals, but also by targeting host defense with NRF2 inducers. Understanding precise molecular mechanisms how the KEAP1-NRF2 system senses and regulates the cellular response is critical to overcome intractable NRF2-activated cancers.

Keywords:  KEAP1; NRF2; cancer therapy; defense system; stress sensing

DOI:  https://doi.org/10.14348/molcells.2023.0028
Front Genet. 2023 ;14 1092276

The construction and analysis of tricarboxylic acid cycle related prognostic model for cervical cancer.

Guanqiao Chen, Xiaoshan Hong, Wanshan He, Lingling Ou, Bin Chen, Weitao Zhong, Yu Lin, Xiping Luo.

  Introduction: Cervical cancer (CC) is the fourth most common malignant tumor in term of in incidence and mortality among women worldwide. The tricarboxylic acid (TCA) cycle is an important hub of energy metabolism, networking one-carbon metabolism, fatty acyl metabolism and glycolysis. It can be seen that the reprogramming of cell metabolism including TCA cycle plays an indispensable role in tumorigenesis and development. We aimed to identify genes related to the TCA cycle as prognostic markers in CC. Methods: Firstly, we performed the differential expressed analysis the gene expression profiles associated with TCA cycle obtained from The Cancer Genome Atlas (TCGA) database. Differential gene list was generated and cluster analysis was performed using genes with detected fold changes >1.5. Based on the subclusters of CC, we analysed the relationship between different clusters and clinical information. Next, Cox univariate and multivariate regression analysis were used to screen genes with prognostic characteristics, and risk scores were calculated according to the genes with prognostic characteristics. Additionally, we analyzed the correlation between the predictive signature and the treatment response of CC patients. Finally, we detected the expression of ench prognostic gene in clinical CC samples by quantitative polymerase chain reaction (RT-qPCR). Results: We constructed a prognostic model consist of seven TCA cycle associated gene (ACSL1, ALDOA, FOXK2, GPI, MDH1B, MDH2, and MTHFD1). Patients with CC were separated into two groups according to median risk score, and high-risk group had a worse prognosis compared to the low-risk group. High risk group had lower level of sensitivity to the conventional chemotherapy drugs including cisplatin, paclitaxel, sunitinib and docetaxel. The expression of ench prognostic signature in clinical CC samples was verified by qRT-PCR. Conclusion: There are several differentially expressed genes (DEGs) related to TCA cycle in CC. The risk score model based on these genes can effectively predict the prognosis of patients and provide tumor markers for predicting the prognosis of CC.

Keywords:  bioinformatics; cervical cancer; metabolic reprogramming; prognostic signature; tricarboxylic acid cycle (TCA cycle)

DOI:  https://doi.org/10.3389/fgene.2023.1092276