bims-glucam 2022-11-13 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2022–11–13
thirteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Probabilistic model checking of cancer metabolism.
Metabolic profiling analysis of head and neck squamous cell carcinoma.
Metabolic Pathways, Enzymes, and Metabolites: Opportunities in Cancer Therapy.
Integrated transcriptomics and metabolomics analyses to investigate the anticancer mechanisms of cinobufagin against liver cancer through interfering with lipid, amino acid, carbohydrate, and nucleotide metabolism.
Metabolomic Signatures in Doxorubicin-Induced Metabolites Characterization, Metabolic Inhibition, and Signaling Pathway Mechanisms in Colon Cancer HCT116 Cells.
2,4-Dinitrophenol as an Uncoupler Augments the Anthracyclines Toxicity against Prostate Cancer Cells.
Advancements in Pulsed Stable Isotope-Resolved Metabolomics.
Relationship between [18F]FDG PET/CT and metabolomics in patients with colorectal cancer.
Mitochondrial dynamics and oxidative phosphorylation as targets in cancer.
Druggable Metabolic Vulnerabilities Are Exposed and Masked during Progression to Castration Resistant Prostate Cancer.
Metabolite activation of tumorigenic signaling pathways in the tumor microenvironment.
The Warburg effect and mitochondrial oxidative phosphorylation: Friends or foes?
Amino acid variability, tradeoffs and optimality in human diet.

Sci Rep. 2022 Nov 07. 12(1): 18870

Probabilistic model checking of cancer metabolism.

Meir D Friedenberg, Adrian Lita, Mark R Gilbert, Mioara Larion, Orieta Celiku.

Cancer cell metabolism is often deregulated as a result of adaption to meeting energy and biosynthesis demands of rapid growth or direct mutation of key metabolic enzymes. Better understanding of such deregulation can provide new insights on targetable vulnerabilities, but is complicated by the difficulty in probing cell metabolism at different levels of resolution and under different experimental conditions. We construct computational models of glucose and glutamine metabolism with focus on the effect of IDH1/2-mutations in cancer using a combination of experimental metabolic flux data and patient-derived gene expression data. Our models demonstrate the potential of computational exploration to reveal biologic behavior: they show that an exogenously-mutated IDH1 experimental model utilizes glutamine as an alternative carbon source for lactate production under hypoxia, but does not fully-recapitulate the patient phenotype under normoxia. We also demonstrate the utility of using gene expression data as a proxy for relative differences in metabolic activity. We use the approach of probabilistic model checking and the freely-available Probabilistic Symbolic Model Checker to construct and reason about model behavior.

DOI: https://doi.org/10.1038/s41598-022-21846-5
Oral Dis. 2022 Nov 08.

Metabolic profiling analysis of head and neck squamous cell carcinoma.

Toshimitsu Ohashi, Kosuke Terazawa, Hirofumi Shibata, Norimitsu Inoue, Takenori Ogawa.

   OBJECTIVE: Tumor cells can acquire a large amount of energy and structural components by reprogramming energy metabolism; moreover, metabolic profiles slightly differ according to cancer type. This study compared and assessed the metabolic profile of head and neck squamous cell carcinoma (HNSCC) and normal tissues, which were collected from patients without cancer.
SUBJECTS AND METHODS: Overall, 23 patients with HNSCC and 6 patients without cancer were included in the analysis. Metabolomic profiles were analyzed using capillary electrophoresis-mass spectrometry. Gene expression was evaluated using real-time reverse transcription-polymerase chain reaction.
RESULTS: Glycolysis, the pentose phosphate pathway, tricarboxylic acid cycle, and glutamine metabolism were upregulated in HNSCC tissues based on gene expression analysis. HNSCC could then have enhanced energy production and structural component. The levels of lactate, succinate, glutathione, 2-hydroxyglutarate, and S-adenosylmethionine, considered as oncometabolites, increased and these had accumulated in HNSCC tissues.
CONCLUSIONS: The level of metabolites and the expression of enzymes differ between HNSCC and normal tissues. Reprogramming metabolism in HNSCC provides an energy source as well as structural components, creating a system that offers rapid proliferation, progression, and is less likely to be eliminated.

Keywords:  head and neck squamous cell carcinoma; metabolic profiling; transcript expression analysis; tumor metabolite; tumor microenvironment

DOI:  https://doi.org/10.1111/odi.14432
Cancers (Basel). 2022 Oct 27. pii: 5268. [Epub ahead of print]14(21):

Metabolic Pathways, Enzymes, and Metabolites: Opportunities in Cancer Therapy.

Rishabh Kumar, Anurag Mishra, Priyanka Gautam, Zainab Feroz, Sivakumar Vijayaraghavalu, Eviania M Likos, Girish C Shukla, Munish Kumar.

  Metabolic reprogramming enables cancer cells to proliferate and produce tumor biomass under a nutrient-deficient microenvironment and the stress of metabolic waste. A cancer cell adeptly undergoes a variety of adaptations in metabolic pathways and differential expression of metabolic enzyme genes. Metabolic adaptation is mainly determined by the physiological demands of the cancer cell of origin and the host tissue. Numerous metabolic regulators that assist cancer cell proliferation include uncontrolled anabolism/catabolism of glucose metabolism, fatty acids, amino acids metabolism, nucleotide metabolism, tumor suppressor genes, microRNAs, and many regulatory enzymes and genes. Using this paradigm, we review the current understanding of metabolic reprogramming in tumors and discuss the new strategies of cancer metabolomics that can be tapped into for cancer therapeutics.

Keywords:  Warburg effect; amino acid metabolism; cancer metabolism; cancer therapeutics; fatty acid metabolism; glycolysis; microRNA; oncogenes; tumor suppressor genes

DOI:  https://doi.org/10.3390/cancers14215268
Bioorg Chem. 2022 Oct 29. pii: S0045-2068(22)00635-6. [Epub ahead of print]130 106229

Integrated transcriptomics and metabolomics analyses to investigate the anticancer mechanisms of cinobufagin against liver cancer through interfering with lipid, amino acid, carbohydrate, and nucleotide metabolism.

Ailin Yang, Qi Wu, Anmei Wang, Qimei Chen, Jingyi Yang, Yufan Tao, Yixuan Sun, Jiayu Zhang.

  Liver cancer has characteristics of high morbidity, high mortality, and poor prognosis. Metabolic reprogramming is a prominent characteristic of tumors and plays a key role in promoting tumorigenesis. The metabolic process of liver cancer cells has undergone many significant changes including abnormal active glycolysis, enhanced de novo synthesis of fatty acids, and hyperactive metabolism of amino acids and nucleotides. Targeting metabolic reprogramming through regulation of anomalously expressed key metabolic enzymes and signaling molecules is considered to be an important strategy for liver cancer treatment. Multi-omics association analyses currently facilitate precise diagnosis, personalized clinical therapy, and revelation of mechanisms of drug action. Cinobufagin, as the major anti-tumor active ingredient of Chansu, the famous chinese medicine used in clinic for cancer treatment, has been reported to exert anticancer effects through many different kinds of mechanisms, but the effects of cinobufagin on metabolic reprogramming of cancer cells still remain unclear. In our study, we identify that cinobufagin exhibits anti-hepatoma effects through interfering with metabolic reprogramming (lipid, amino acid, carbohydrate, and nucleotide metabolism) based on integrated transcriptomics and metabolomics analyses. Furthermore, the results of integrated multi-omics analyses enrich various core regulatory mechanisms of anti-tumor effects of cinobufagin which are associated with metabolic pathway. In addition, some verifications of the enriched mechanisms related to intervention of lipid and carbohydrate metabolism in response to cinobufagin are also performed. This work will promote the innovation of the research model of TCM, and lay a solid theoretical foundation for the clinical application of cinobufagin and Chansu.

Keywords:  Cinobufagin; Integrated transcriptomics and metabolomics analyses; Liver cancer; Metabolic reprogramming

DOI:  https://doi.org/10.1016/j.bioorg.2022.106229
Metabolites. 2022 Oct 31. pii: 1047. [Epub ahead of print]12(11):

Metabolomic Signatures in Doxorubicin-Induced Metabolites Characterization, Metabolic Inhibition, and Signaling Pathway Mechanisms in Colon Cancer HCT116 Cells.

Raja Ganesan, Vasantha-Srinivasan Prabhakaran, Abilash Valsala Gopalakrishnan.

  Doxorubicin (DOX) is a chemotherapeutic agent is used for various cancer cells. To characterize the chemical structural components and metabolic inhibition, we applied a DOX to HCT116 colon cancer cells using an independent metabolites profiling approach. Chemical metabolomics has been involved in the new drug delivery systems. Metabolomics profiling of DOX-applied HCT116 colon cancer cellular metabolisms is rare. We used 1H nuclear magnetic resonance (NMR) spectroscopy in this study to clarify how DOX exposure affected HCT116 colon cancer cells. Metabolomics profiling in HCT116 cells detects 50 metabolites. Tracking metabolites can reveal pathway activities. HCT116 colon cancer cells were evenly treated with different concentrations of DOX for 24 h. The endogenous metabolites were identified by comparison with healthy cells. We found that acetate, glucose, glutamate, glutamine, sn-glycero-3-phosphocholine, valine, methionine, and isoleucine were increased. Metabolic expression of alanine, choline, fumarate, taurine, o-phosphocholine, inosine, lysine, and phenylalanine was decreased in HCT116 cancer cells. The metabolic phenotypic expression is markedly altered during a high dose of DOX. It is the first time that there is a metabolite pool and phenotypic expression in colon cancer cells. Targeting the DOX-metabolite axis may be a novel strategy for improving the curative effect of DOX-based therapy for colon cancer cells. These methods facilitate the routine metabolomic analysis of cancer cells.

Keywords:  HCT116 cells; NMR; colorectal cancer; doxorubicin; metabolic profiling; metabolomics

DOI:  https://doi.org/10.3390/metabo12111047
Molecules. 2022 Oct 25. pii: 7227. [Epub ahead of print]27(21):

2,4-Dinitrophenol as an Uncoupler Augments the Anthracyclines Toxicity against Prostate Cancer Cells.

Grzegorz Adamczuk, Ewelina Humeniuk, Kamila Adamczuk, Aneta Grabarska, Jarosław Dudka.

  One of the strategies for the treatment of advanced cancer diseases is targeting the energy metabolism of the cancer cells. The compound 2,4-DNP (2,4-dinitrophenol) disrupts the cell energy metabolism through the ability to decouple oxidative phosphorylation. The aim of the study was to determine the ability of 2,4-DNP to sensitize prostate cancer cells with different metabolic phenotypes to the action of known anthracyclines (doxorubicin and epirubicin). The synergistic effect of the anthracyclines and 2,4-DNP was determined using an MTT assay, apoptosis detection and a cell cycle analysis. The present of oxidative stress in cancer cells was assessed by CellROX, the level of cellular thiols and DNA oxidative damage. The study revealed that the incubation of LNCaP prostate cancer cells (oxidative phenotype) with epirubicin and doxorubicin simultaneously with 2,4-DNP showed the presence of a synergistic effect for both the cytostatics. Moreover, it contributes to the increased induction of oxidative stress, which results in a reduced level of cellular thiols and an increased number of AP sites in the DNA. The synergistic activity may consist of an inhibition of ATP synthesis and the simultaneous production of toxic amounts of ROS, destroying the mitochondria. Additionally, the sensitivity of the LNCaP cell line to the anthracyclines is relatively higher compared to the other two (PC-3, DU-145).

Keywords:  2,4-dinitrophenol; anthracyclines; doxorubicin; epirubicin; prostate cancer; uncoupler

DOI:  https://doi.org/10.3390/molecules27217227
Handb Exp Pharmacol. 2022 Nov 11.

Advancements in Pulsed Stable Isotope-Resolved Metabolomics.

Martin Forbes, Sabrina Geisberger, Matthias Pietzke, Guido Mastrobuoni, Stefan Kempa.

  The understanding of biochemical processes of metabolism is gained through the measurement of the concentration of intermediates and the rate of metabolite conversion. However, the measurement of metabolite concentrations does not give a full representation of this dynamic system. To understand the kinetics of metabolism, the system must be described and quantified in terms of metabolite flow as a function of time. In order to measure the metabolite flow, or more precisely the metabolic flux through a biological system, substrates of the cell are labelled with stable isotopes. The usage of these substrates by the cell leads to the incorporation of the isotopes into downstream intermediates.The most important metabolic pathways are encompassed in the central carbon metabolism (CCM). According to the Kyoto Encyclopedia of Genes and Genomes (KEGG), the central carbon metabolism "is the most basic aspect of life". It includes all metabolites and enzymatic reactions within: glycolysis and gluconeogenesis, pentose phosphate pathway (PPP), tricarboxylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS), amino acids and nucleotide metabolic pathways. Some molecules are at the crossroad of metabolic pathways, interconnecting diverse metabolic and therefore functional outcomes. Labelling these nodal metabolites and analysing their isotopic composition allows the precise determination of the metabolic flow within the biochemical networks that they are in.Application of stable isotope labelled substrates allows the measurement of metabolic flux through a biochemical pathway. The rapid turnover of metabolites in pathways requires pulse-feeding cells with a labelled substrate. This method allows for the determination of different cell states. For example, the action of a drug from immediate impact until the compensatory response of the metabolic system (cell, organs, organisms). Pulsed labelling is an elegant way to analyse the action of small molecules and drugs and enables the analysis of regulatory metabolic processes in short time scales.

Keywords:  Cancer metabolism; Isotope-resolved metabolomics; Mass spectrometry methods; Metabolic flux analysis

DOI:  https://doi.org/10.1007/164_2022_621
Metabolomics. 2022 Nov 11. 18(11): 91

Relationship between [18F]FDG PET/CT and metabolomics in patients with colorectal cancer.

Masashi Imajo, Takashi Norikane, Yuka Yamamoto, Yukito Maeda, Kaori Saitoh, Keiko Kato, Tomoyoshi Soga, Keiichi Okano, Yoshihiro Nishiyama.

   INTRODUCTION: Advances in metabolomics have significantly improved cancer detection, diagnosis, treatment, and prognosis.
OBJECTIVES: To investigate the relationship between metabolic tumor volume (MTV) using 2-deoxy-2-[18F]fluoro-D-glucose (FDG) positron emission tomography (PET)/ computed tomography (CT) and metabolomics data in patients with colorectal cancer (CRC).
METHODS: The metabolome in tumor tissues was analyzed using capillary electrophoresis time-of-flight mass spectrometry in 33 patients with newly diagnosed CRC who underwent FDG PET/CT before treatment and had tumor tissue post-surgery. Based on the FDG PET data, MTV was calculated and was dichotomized according to the median value, and tumors were divided into low-MTV and high-MTV tumors. Metabolomics data were compared between the low-MTV and high-MTV tumors.
RESULTS: The levels of most glycolysis-related metabolites were not different between low-MTV and high-MTV tumors. The level of component of the initial part of the tricarboxylic acid (TCA) cycle, citrate, was significantly lower in the high-MTV tumor than in the low-MTV tumor. The TCA intermediate succinate level was significantly higher in the high-MTV tumor than in the low-MTV tumor. In contrast, the TCA intermediate fumarate level was significantly lower in the high-MTV tumor than in the low-MTV tumor. The levels of many amino acids were significantly higher in the high-MTV tumor than in the low-MTV tumor.
CONCLUSIONS: Although preliminary, these results suggest that tumors with high FDG metabolism in CRC may obtain more energy by using a reverse reaction of the TCA cycle and amino-acid metabolism. However, further research is required to clarify this relationship.

Keywords:  Colorectal cancer; FDG; Metabolome; PET/CT

DOI:  https://doi.org/10.1007/s11306-022-01952-1
Endocr Relat Cancer. 2022 Nov 01. pii: ERC-22-0229. [Epub ahead of print]

Mitochondrial dynamics and oxidative phosphorylation as targets in cancer.

Kaylee B Punter, Charles Chu, Edmond Y W Chan.

It has long been recognised that cancer cells critically depend on reprogrammed patterns of metabolism that can enable robust and abnormally high levels of cell proliferation. As mitochondria form hubs of cellular metabolic activity, it is reasonable to propose that pathways within these organelles can form targets that can be manipulated to compromise the ability of cancer cells to cause disease. However, mitochondria are highly multi-functional and the full range of mechanistic inter-connections are still being unraveled to enable the full potential of targeting mitochondria in cancer therapeutics. Here, we aim to highlight the potential of modulating mitochondrial dynamics to target key metabolic or apoptotic pathways in cancer cells. Distinct roles have been demonstrated for mitochondrial fission and fusion in different cancer contexts. Targeting of factors mediating mitochondrial dynamics may be directly related to impairment of oxidative phosphorylation, which is essential to sustain cancer cell growth and can also alter sensitivity to chemotherapeutic compounds. This area is still lacking a unified model although further investigation will more comprehensively map the underlying molecular mechanisms to enable better rational therapeutic strategies based on these pathways.

DOI: https://doi.org/10.1530/ERC-22-0229
Biomolecules. 2022 Oct 28. pii: 1590. [Epub ahead of print]12(11):

Druggable Metabolic Vulnerabilities Are Exposed and Masked during Progression to Castration Resistant Prostate Cancer.

Stephen Y C Choi, Caroline Fidalgo Ribeiro, Yuzhuo Wang, Massimo Loda, Stephen R Plymate, Takuma Uo.

  There is an urgent need for exploring new actionable targets other than androgen receptor to improve outcome from lethal castration-resistant prostate cancer. Tumor metabolism has reemerged as a hallmark of cancer that drives and supports oncogenesis. In this regard, it is important to understand the relationship between distinctive metabolic features, androgen receptor signaling, genetic drivers in prostate cancer, and the tumor microenvironment (symbiotic and competitive metabolic interactions) to identify metabolic vulnerabilities. We explore the links between metabolism and gene regulation, and thus the unique metabolic signatures that define the malignant phenotypes at given stages of prostate tumor progression. We also provide an overview of current metabolism-based pharmacological strategies to be developed or repurposed for metabolism-based therapeutics for castration-resistant prostate cancer.

Keywords:  Warburg’s effect; androgen receptor; cancer metabolism; drug resistance; fatty acids; lactate; prostate cancer

DOI:  https://doi.org/10.3390/biom12111590
Sci Signal. 2022 Nov 08. 15(759): eabj4220

Metabolite activation of tumorigenic signaling pathways in the tumor microenvironment.

Vivien Low, Zhongchi Li, John Blenis.

The role of metabolites exchanged in the tumor microenvironment is largely thought of as fuels to drive the increased biosynthetic and bioenergetic demands of growing tumors. However, this view is shifting as metabolites are increasingly shown to function as signaling molecules that directly regulate oncogenic pathways. Combined with our growing understanding of the essential role of stromal cells, this shift has led to increased interest in how the collective and interconnected metabolome of the tumor microenvironment can drive malignant transformation, epithelial-to-mesenchymal transition, drug resistance, immune evasion, and metastasis. In this review, we discuss how metabolite exchange between tumors and various cell types in the tumor microenvironment-such as fibroblasts, adipocytes, and immune cells-can activate signaling pathways that drive cancer progression.

DOI: https://doi.org/10.1126/scisignal.abj4220
Biochim Biophys Acta Bioenerg. 2022 Oct 29. pii: S0005-2728(22)00401-7. [Epub ahead of print]1864(1): 148931

The Warburg effect and mitochondrial oxidative phosphorylation: Friends or foes?

M Martins Pinto, P Paumard, C Bouchez, S Ransac, S Duvezin-Caubet, J P Mazat, M Rigoulet, A Devin.

  Cancer cells display an altered energy metabolism, which was proposed to be the root of cancer. This early discovery was done by O. Warburg who conducted one of the first studies of tumor cell energy metabolism. Taking advantage of cancer cells that exhibited various growth rates, he showed that cancer cells display a decreased respiration and an increased glycolysis proportional to the increase in their growth rate, suggesting that they mainly depend on fermentative metabolism for ATP generation. Warburg's results and hypothesis generated controversies that are persistent to this day. It is thus of great importance to understand the mechanisms by which cancer cells can reversibly regulate the two pathways of their energy metabolism as well as the functioning of this metabolism in cell proliferation. In this review, we discuss of the origin of the decrease in cell respiratory rate, whether the Warburg effect is mandatory for an increased cell proliferation rate, the consequences of this effect on two major players of cell energy metabolism that are ATP and NADH, and the role of the microenvironment in the regulation of cellular respiration and metabolism both in cancer cell and in yeast.

Keywords:  Cancer; Mitochondria; Oxidative phosphorylation; Warburg effect

DOI:  https://doi.org/10.1016/j.bbabio.2022.148931
Nat Commun. 2022 Nov 05. 13(1): 6683

Amino acid variability, tradeoffs and optimality in human diet.

Ziwei Dai, Weiyan Zheng, Jason W Locasale.

Studies at the molecular level demonstrate that dietary amino acid intake produces substantial effects on health and disease by modulating metabolism. However, how these effects may manifest in human food consumption and dietary patterns is unknown. Here, we develop a series of algorithms to map, characterize and model the landscape of amino acid content in human food, dietary patterns, and individual consumption including relations to health status, covering over 2,000 foods, ten dietary patterns, and over 30,000 dietary profiles. We find that the type of amino acids contained in foods and human consumption is highly dynamic with variability far exceeding that of fat and carbohydrate. Some amino acids positively associate with conditions such as obesity while others contained in the same food negatively link to disease. Using linear programming and machine learning, we show that these health trade-offs can be accounted for to satisfy biochemical constraints in food and human eating patterns to construct a Pareto front in dietary practice, a means of achieving optimality in the face of trade-offs that are commonly considered in economic and evolutionary theories. Thus this study may enable the design of human protein quality intake guidelines based on a quantitative framework.

DOI: https://doi.org/10.1038/s41467-022-34486-0