bims-glucam 2023-11-26 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2023‒11‒26
nine papers selected by
Sreeparna Banerjee, Middle East Technical University

Determination of Metabolic Fluxes by Deep Learning of Isotope Labeling Patterns.
Glutamine synthetase and hepatocellular carcinoma.
Glucose-6-phosphate dehydrogenase deficiency accelerates pancreatic acinar-to-ductal metaplasia.
The Interaction between Collagen 1 and High Mannose Type CD133 Up-Regulates Glutamine Transporter SLC1A5 to Promote the Tumorigenesis of Glioblastoma Stem Cells.
Phytochemicals Target Multiple Metabolic Pathways in Cancer.
The Key Role of GSH in Keeping the Redox Balance in Mammalian Cells: Mechanisms and Significance of GSH in Detoxification via Formation of Conjugates.
Clinical, Functional, and Nutritional Efficacy of a Glutamine-Enriched Oligomeric Diet in Patients with Rectal Cancer.
Amino acids and cancer: potential for therapies?
A century of the Warburg effect.

bioRxiv. 2023 Nov 08. pii: 2023.11.06.565907. [Epub ahead of print]

Determination of Metabolic Fluxes by Deep Learning of Isotope Labeling Patterns.

Richard C Law, Samantha O'Keeffe, Glenn Nurwono, Rachel Ki, Aliya Lakhani, Pin-Kuang Lai, Junyoung O Park.

Fluxomics offers a direct readout of metabolic state but relies on indirect measurement. Stable isotope tracers imprint flux-dependent isotope labeling patterns on metabolites we measure; however, the relationship between labeling patterns and fluxes remains elusive. Here we innovate a two-stage machine learning framework termed ML-Flux that streamlines metabolic flux quantitation from isotope tracing. We train machine learning models by simulating atom transitions across five universal metabolic models starting from 26 13 C-glucose, 2 H-glucose, and 13 C-glutamine tracers within feasible flux space. ML-Flux employs deep-learning-based imputation to take variable measurements of labeling patterns as input and successive neural networks to convert the ensuing comprehensive labeling information into metabolic fluxes. Using ML-Flux with multi-isotope tracing, we obtain fluxes through central carbon metabolism that are comparable to those from a least-squares method but orders-of-magnitude faster. ML-Flux is deployed as a webtool to expand the accessibility of metabolic flux quantitation and afford actionable information on metabolism.

DOI: https://doi.org/10.1101/2023.11.06.565907
Clin Res Hepatol Gastroenterol. 2023 Nov 16. pii: S2210-7401(23)00173-0. [Epub ahead of print]47(10): 102248

Glutamine synthetase and hepatocellular carcinoma.

Jinghua Jiang, Yiting Hu, Dazhang Fang, JianSheng Luo.

  Glutamine synthetase (GS) is an enzyme that converts ammonia and glutamate to glutamine using adenosine triphosphate. GS is expressed in the brain, kidney, and liver tissues under normal physiological conditions. GS is involved in abnormal lipid metabolism of the liver by catalyzing de novo synthesis of glutamine, thereby inducing liver inflammation. Metabolic dysfunction-associated steatotic liver diseases (MASLD), such as Metabolic Associated Fatty Liver Disease and Metabolic Associated Steato Hepatitis, are considered risk factors for HCC. GS may also be involved in the development and progression of hepatocellular carcinoma (HCC) through other signaling pathways, including the rapamycin (mTOR) and Wnt/β-catenin signaling pathways. Furthermore, the correct combination of HSP70, GPC3, and GS can improve the accuracy and precision of HCC diagnosis. However, the prognostic value of GS in different HCC populations remains controversial. The expression of GS affects the sensitivity of HCC cells to radiotherapy and chemotherapy. In addition, immunotherapy has been approved for the treatment of advanced HCC. This article delves into the development and application of GS in HCC, laying a theoretical foundation for the subsequent exploration of GS as a potential target for treating HCC.

Keywords:  Biomarkers; Glutamine; Glutamine synthetase; Primary hepatocellular carcinoma

DOI:  https://doi.org/10.1016/j.clinre.2023.102248
bioRxiv. 2023 Nov 08. pii: 2023.11.06.565895. [Epub ahead of print]

Glucose-6-phosphate dehydrogenase deficiency accelerates pancreatic acinar-to-ductal metaplasia.

Megan D Radyk, Barbara S Nelson, Christopher J Halbrook, Alexander Wood, Brooke Lavoie, Lucie Salvatore, Gabriel Corfas, Justin A Colacino, Yatrik M Shah, Howard C Crawford, Costas A Lyssiotis.

Activating mutations in KRAS extensively reprogram cellular metabolism to support the continuous growth, proliferation, and survival of pancreatic tumors. Targeting these metabolic dependencies are promising approaches for the treatment of established tumors. However, metabolic reprogramming is required early during tumorigenesis to provide transformed cells selective advantage towards malignancy. Acinar cells can give rise to pancreatic tumors through acinar-to-ductal metaplasia (ADM). Dysregulation of pathways that maintain acinar homeostasis accelerate tumorigenesis. During ADM, acinar cells transdifferentiate to duct-like cells, a process driven by oncogenic KRAS . The metabolic reprogramming that is required for the transdifferentiation in ADM is unclear. We performed transcriptomic analysis on mouse acinar cells undergoing ADM and found metabolic programs are globally enhanced, consistent with the transition of a specialized cell to a less differentiated phenotype with proliferative potential. Indeed, we and others have demonstrated how inhibiting metabolic pathways necessary for ADM can prevent transdifferentiation and tumorigenesis. Here, we also find NRF2-target genes are differentially expressed during ADM. Among these, we focused on the increase in the gene coding for NADPH-producing enzyme, Glucose-6-phosphate dehydrogenase (G6PD). Using established mouse models of Kras G12D -driven pancreatic tumorigenesis and G6PD-deficiency, we find that mutant G6pd accelerates ADM and pancreatic intraepithelial neoplasia. Acceleration of cancer initiation with G6PD-deficiency is dependent on its NADPH-generating function in reactive oxygen species (ROS) management, as opposed to other outputs of the pentose phosphate pathway. Together, this work provides new insights into the function of metabolic pathways during early tumorigenesis.

DOI: https://doi.org/10.1101/2023.11.06.565895
Adv Sci (Weinh). 2023 Nov 23. e2306715

The Interaction between Collagen 1 and High Mannose Type CD133 Up-Regulates Glutamine Transporter SLC1A5 to Promote the Tumorigenesis of Glioblastoma Stem Cells.

Yuanyan Wei, Shuting Geng, Yu Si, Yuerong Yang, Qihang Chen, Sijing Huang, Xiaoning Chen, Wenlong Xu, Yinchao Liu, Jianhai Jiang.

  Targeting the niche components surrounding glioblastoma stem cells (GSCs) helps to develop more effective glioblastoma treatments. However, the mechanisms underlying the crosstalk between GSCs and microenvironment remain largely unknown. Clarifying the extracellular molecules binding to GSCs marker CD133 helps to elucidate the mechanism of the communication between GSCs and the microenvironment. Here, it is found that the extracellular domain of high mannose type CD133 physically interacts with Collagen 1 (COL1) in GSCs. COL1, mainly secreted by cancer-associated fibroblasts, is a niche component for GSCs. COL1 enhances the interaction between CD133 and p85 and activates Akt phosphorylation. Activation of Akt pathway increases transcription factor ATF4 protein level, subsequently enhances SLC1A5-dependent glutamine uptake and glutathione synthesis. The inhibition of CD133-COL1 interaction or down-regulation of SLC1A5 reduces COL1-accelerated GSCs self-renewal and tumorigenesis. Analysis of glioma samples reveals that the level of COL1 is correlated with histopathological grade of glioma and the expression of SLC1A5. Collectively, COL1, a niche component for GSCs, enhances the tumorigenesis of GSCs partially through CD133-Akt-SLC1A5 signaling axis, providing a new mechanism underlying the cross-talk between GSCs and extracellular matrix (ECM) microenvironment.

Keywords:  CD133; COL1; SLC1A5; glioma stem cell; tumorigenesis

DOI:  https://doi.org/10.1002/advs.202306715
Antioxidants (Basel). 2023 Nov 17. pii: 2012. [Epub ahead of print]12(11):

Phytochemicals Target Multiple Metabolic Pathways in Cancer.

Oleg Shuvalov, Yulia Kirdeeva, Alexandra Daks, Olga Fedorova, Sergey Parfenyev, Hans-Uwe Simon, Nickolai A Barlev.

  Cancer metabolic reprogramming is a complex process that provides malignant cells with selective advantages to grow and propagate in the hostile environment created by the immune surveillance of the human organism. This process underpins cancer proliferation, invasion, antioxidant defense, and resistance to anticancer immunity and therapeutics. Perhaps not surprisingly, metabolic rewiring is considered to be one of the "Hallmarks of cancer". Notably, this process often comprises various complementary and overlapping pathways. Today, it is well known that highly selective inhibition of only one of the pathways in a tumor cell often leads to a limited response and, subsequently, to the emergence of resistance. Therefore, to increase the overall effectiveness of antitumor drugs, it is advisable to use multitarget agents that can simultaneously suppress several key processes in the tumor cell. This review is focused on a group of plant-derived natural compounds that simultaneously target different pathways of cancer-associated metabolism, including aerobic glycolysis, respiration, glutaminolysis, one-carbon metabolism, de novo lipogenesis, and β-oxidation of fatty acids. We discuss only those compounds that display inhibitory activity against several metabolic pathways as well as a number of important signaling pathways in cancer. Information about their pharmacokinetics in animals and humans is also presented. Taken together, a number of known plant-derived compounds may target multiple metabolic and signaling pathways in various malignancies, something that bears great potential for the further improvement of antineoplastic therapy.

Keywords:  cancer metabolism; glutaminolysis; glycolysis; lipid metabolism; metabolic reprogramming and plasticity; multitarget agents; natural compounds; one-carbon metabolism; β-oxidation of fatty acids

DOI:  https://doi.org/10.3390/antiox12112012
Antioxidants (Basel). 2023 Nov 01. pii: 1953. [Epub ahead of print]12(11):

The Key Role of GSH in Keeping the Redox Balance in Mammalian Cells: Mechanisms and Significance of GSH in Detoxification via Formation of Conjugates.

Sofia K Georgiou-Siafis, Asterios S Tsiftsoglou.

  Glutathione (GSH) is a ubiquitous tripeptide that is biosynthesized in situ at high concentrations (1-5 mM) and involved in the regulation of cellular homeostasis via multiple mechanisms. The main known action of GSH is its antioxidant capacity, which aids in maintaining the redox cycle of cells. To this end, GSH peroxidases contribute to the scavenging of various forms of ROS and RNS. A generally underestimated mechanism of action of GSH is its direct nucleophilic interaction with electrophilic compounds yielding thioether GSH S-conjugates. Many compounds, including xenobiotics (such as NAPQI, simvastatin, cisplatin, and barbital) and intrinsic compounds (such as menadione, leukotrienes, prostaglandins, and dopamine), form covalent adducts with GSH leading mainly to their detoxification. In the present article, we wish to present the key role and significance of GSH in cellular redox biology. This includes an update on the formation of GSH-S conjugates or GSH adducts with emphasis given to the mechanism of reaction, the dependence on GST (GSH S-transferase), where this conjugation occurs in tissues, and its significance. The uncovering of the GSH adducts' formation enhances our knowledge of the human metabolome. GSH-hematin adducts were recently shown to have been formed spontaneously in multiples isomers at hemolysates, leading to structural destabilization of the endogenous toxin, hematin (free heme), which is derived from the released hemoglobin. Moreover, hemin (the form of oxidized heme) has been found to act through the Kelch-like ECH associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor-2 (Nrf2) signaling pathway as an epigenetic modulator of GSH metabolism. Last but not least, the implications of the genetic defects in GSH metabolism, recorded in hemolytic syndromes, cancer and other pathologies, are presented and discussed under the framework of conceptualizing that GSH S-conjugates could be regarded as signatures of the cellular metabolism in the diseased state.

Keywords:  GSH S-conjugates; GSH adducts; GSH metabolism; GSH redox cycle; GSH-hematin adducts; GSTs; hemolytic disorders; metabolic signatures; thioether bonds; xenobiotics

DOI:  https://doi.org/10.3390/antiox12111953
Nutr Cancer. 2023 Nov 23. 1-9

Clinical, Functional, and Nutritional Efficacy of a Glutamine-Enriched Oligomeric Diet in Patients with Rectal Cancer.

Johanna Del Carmen Peña Vivas, Andrea Carolina Orduz Arena, Ana Alonso García, Carlos Fernando Carrascal Gordillo, Rocío Martínez Gutiérrez, Cristina Rodríguez-Acosta Caballero, Ignacio Fernández Freije, Ana Belén Paino Martínez, Tamara Belloso Cuesta, Germán Juan Rijo, Alicia Calleja Fernández.

AIMS: This work aims to evaluate the efficacy of nutritional supplementation with a glutamine-enriched oligomeric diet (GEOD) compared to a standard polymeric diet (SPD) in terms of oncology treatment-related diarrhea (OTRD) (frequency and consistency of stools), gastrointestinal toxicity, and functional and nutritional progress.METHODS: This prospective cohort study compared two groups of patients with rectal cancer in treatment with neoadjuvant chemotherapy and radiotherapy who were at risk of malnutrition. Patients were randomized to receive either 400 ml of GEOD or of SPD from the start of radiotherapy to 30 days after its completion.
RESULTS: Eighty patients were recruited, 40 per arm. The GEOD arm had improved stool consistency and a greater reduction in the number of stools compared to the SPD arm (p < 0.001). The relative risk (RR) of developing diarrhea in the GEOD arm was 0.059 (95% CI 0.015-0.229). There was a reduced risk of developing intestinal mucositis in the GEOD arm compared to the SPD arm [RR 0.202 (95% CI 0.102 - 0.399)]. The GEOD arm had greater improvements in functional and nutritional status (p < 0.001).
CONCLUSIONS: GEOD had a protective effect in terms of the development of gastrointestinal toxicity associated with chemotherapy and radiotherapy treatment in patients with rectal cancer.

DOI: https://doi.org/10.1080/01635581.2023.2286698
Curr Opin Clin Nutr Metab Care. 2023 Nov 27.

Amino acids and cancer: potential for therapies?

Jéssika M Siqueira, Maria C M Dela Vega, Gustavo D Pimentel.

PURPOSE OF REVIEW: Cancer patients may have a variety of disorders associated with systemic inflammation caused by disease progression. Consequently, we have protein hypercatabolism. In view of this, protein and amino acid adequacy should be considered in relation to nutritional behavior. Therefore, this review aims to evaluate the influence of protein and amino acids in the nutritional therapy of cancer.RECENT FINDINGS: Diets with adequate protein levels appear to be beneficial in the treatment of cancer; guidelines suggest consumption of greater than 1.0-1.5 g/kg body weight/day. In patients diagnosed with malnutrition, sarcopenia, or cachexia, it is recommended to use the maximum amount of protein (1.5 g/kg of weight/day) to adapt the diet. In addition, based on the evidence found, there is no consensus on the dose and effects in cancer patients of amino acids such as branched-chain amino acids, glutamine, arginine, and creatine.
SUMMARY: When evaluating the components of the diet of cancer patients, the protein recommendation should be greater than 1.0-1.5 g/kg of weight/day, with a distribution between animal and vegetable proteins. We found little evidence demonstrating clinical benefits regarding individual or combined amino acid supplementation. Still, it is unclear how the use, dose, and specificity for different types of cancer should be prescribed or at what stage of treatment amino acids should be prescribed.

DOI: https://doi.org/10.1097/MCO.0000000000000998
Nat Metab. 2023 Nov;5(11): 1840-1843

A century of the Warburg effect.

Craig B Thompson, Karen H Vousden, Randall S Johnson, Willem H Koppenol, Helmut Sies, Zhimin Lu, Lydia W S Finley, Christian Frezza, Jiyeon Kim, Zeping Hu, Caroline R Bartman.

DOI: https://doi.org/10.1038/s42255-023-00927-3