bims-glucam 2023-08-13 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2023–08–13
thirteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Pancreatic ductal adenocarcinoma chemoresistance: from metabolism reprogramming to novel treatment.
The key role of glutamine for protein expression and isotopic labeling in insect cells.
Non-ammoniagenic proliferation and differentiation media for cultivated adipose tissue.
Upregulation of ubiquitin carboxy‑terminal hydrolase 47 (USP47) in papillary thyroid carcinoma ex vivo and reduction of tumor cell malignant behaviors after USP47 knockdown by stabilizing SATB1 expression in vitro.
Effects of glutamine on plasma protein and inflammation in postoperative patients with colorectal cancer: a meta-analysis of randomized controlled trials.
Emerging therapies in cancer metabolism.
Breast cancers as ecosystems: a metabolic perspective.
Extracellular Matrix Collagen I Differentially Regulates the Metabolic Plasticity of Pancreatic Ductal Adenocarcinoma Parenchymal Cell and Cancer Stem Cell.
Cellular Adaptation Takes Advantage of Atavistic Regression Programs during Carcinogenesis.
Insights into the Tumor-Stromal-Immune Cell Metabolism Crosstalk in Ovarian Cancer.
Glucose Deprivation Induces Cancer Cell Death through Failure of ROS Regulation.
Cancer Metabolism Historical Perspectives: A Chronicle of Controversies and Consensus.
Amino Acid Metabolism and Disease.

Chin Med J (Engl). 2023 Aug 04.

Pancreatic ductal adenocarcinoma chemoresistance: from metabolism reprogramming to novel treatment.

Jingcheng Zhang, Yutong Wang, Lejunzi Wang, Lei You, Taiping Zhang.

ABSTRACT: As pancreatic cancer (PC) is highly malignant, its patients tend to develop metastasis at an early stage and show a poor response to conventional chemotherapies. First-line chemotherapies for PC, according to current guidelines, include fluoropyrimidine- and gemcitabine-based regimens. Accumulating research on drug resistance has shown that biochemical metabolic aberrations in PC, especially those involving glycolysis and glutamine metabolism, are highly associated with chemoresistance. Additionally, lipid metabolism is a major factor in chemoresistance. However, emerging compounds that target these key metabolic pathways have the potential to overcome chemoresistance. This review summarizes how PC develops chemoresistance through aberrations in biochemical metabolism and discusses novel critical targets and pathways within cancer metabolism for new drug research.

DOI: https://doi.org/10.1097/CM9.0000000000002758
J Biol Chem. 2023 Aug 06. pii: S0021-9258(23)02170-1. [Epub ahead of print] 105142

The key role of glutamine for protein expression and isotopic labeling in insect cells.

Feng-Jie Wu, Domenic Kronenberg, Ines Hertel, Stephan Grzesiek.

  NMR studies of many physiologically important proteins have long been impeded by the necessity to express such proteins in isotope-labeled form in higher eukaryotic cells and the concomitant high costs of providing isotope-labeled amino acids in the growth medium. Economical routes use isotope-labeled yeast or algae extracts, but still require expensive isotope-labeled glutamine. Here, we have systematically quantified the effect of 15N2-glutamine on the expression and isotope labeling of different proteins in insect cells. Sufficient levels of glutamine in the medium increase the protein expression by four to five times relative to deprived conditions. 1H-15N NMR spectroscopy shows that the 15N atoms from 15N2-glutamine are scrambled with surprisingly high (60-70%) efficiency into the three amino acids alanine, aspartate, and glutamate. This phenomenon gives direct evidence that the high energy demand of insect cells during baculovirus infection and concomitant heterologous protein expression is predominantly satisfied by glutamine feeding the TCA cycle. To overcome the high costs of supplementing isotope-labeled glutamine, we have developed a robust method for the large-scale synthesis of 15N2-glutamine and partially deuterated 15N2-glutamine-α,β,β-d3 from inexpensive precursors. An application is shown for the effective large-scale expression of the isotope-labeled β1-adrenergic receptor using the synthesized 15N2-glutamine-α,β,β-d3.

Keywords:  Abelson kinase; G protein-coupled receptor; NMR; glutamine; green fluorescent protein; insect cells; isotope labeling; tricarboxylic acid cycle

DOI:  https://doi.org/10.1016/j.jbc.2023.105142
Front Bioeng Biotechnol. 2023 ;11 1202165

Non-ammoniagenic proliferation and differentiation media for cultivated adipose tissue.

S Hubalek, J Melke, P Pawlica, M J Post, P Moutsatsou.

  Ammonia (Amm), and its aqueous solved state, ammonium, which is produced from glutamine (Gln) metabolism, is a known inhibitor of stem cell proliferation in vitro. In the context of cultivated beef, primary bovine fibro-adipogenic progenitor cells (FAPs) need to be grown and differentiated for several weeks in vitro for the production of cultivated fat. In this study, the ammonium sensitivity of these cells was investigated by introducing ammonium chloride, which was found to inhibit their proliferation when above 5 mM and their adipogenic differentiation when above 2 mM. Novel serum-free proliferation and differentiation media were hence developed with the aim to suppress Amm production during expansion and adipogenesis. Glutamine substitutes, such as a-ketoglutarate (aKG), glutamate (Glt) and pyruvate (Pyr) were investigated. It was found that aKG based proliferation medium (PM) was the most effective in promoting and maintaining FAPs growth over several passages while the specific Amm production rate was reduced more than 5-fold. In terms of differentiation capacity, the substitution of glucose (Gluc) and Gln with galactose (Gal) and Pyr was shown to be the most effective in promoting FAPs differentiation into mature adipocytes, resulting in over 2-fold increase of fat volume per cell, while suppressing Amm production. Our findings suggest that FAPs do not require Gln as an essential nutrient but, on the contrary, possess all the necessary metabolic pathways to proliferate and subsequently differentiate in a Gln-free medium, resulting in decreased Amm production rates and seemingly synthesising glutamine de novo. These findings are important for prolonging the lifespan of culture medium, allowing for reduced costs and process interventions.

Keywords:  adipogenic medium; ammonia inhibition; ammonia-free cell culture; cultured meat; glutamine substitution

DOI:  https://doi.org/10.3389/fbioe.2023.1202165
Oncol Lett. 2023 Sep;26(3): 370

Upregulation of ubiquitin carboxy‑terminal hydrolase 47 (USP47) in papillary thyroid carcinoma ex vivo and reduction of tumor cell malignant behaviors after USP47 knockdown by stabilizing SATB1 expression in vitro.

Guirong Luo, Liting Zhang, Wenyi Wu, Lihong Zhang, Jianqing Lin, Haihong Shi, Xinquan Wu, Yihuang Yu, Weigang Qiu, Jinyan Chen, Hansen Ding, Xinyao Chen.

  Aberrant ubiquitination contributes to cancer development, including thyroid carcinoma. The present study assessed the expression of ubiquitin carboxy-terminal hydrolase 47 (USP47) and underlying molecular events in the development of papillary thyroid carcinoma (PTC). The effects of USP47 on PTC cell invasion and migration were analyzed by Transwell assays, while. the effects of USP47 and SATB1on PTC cell gene expression and changes in tumor cell metabolism were assayed by reverse transcription-quantitative PCR, western bolt, or ELISA, respectively. The expression of USP47 mRNA and protein was upregulated in PTC tissue and associated with the PTC tumor size. Knockdown of USP47 expression in PTC cell lines (TPC-1 and K1), decreased the cell proliferation mobility and invasion capacities, whereas USP47 overexpression in these cell lines showed an inverse effect and promoted cell glycolysis and glutamine metabolism. Moreover, expression of special AT-rich sequence-binding protein-1 (SATB1) was high in PTC tissue and was associated with USP47 expression. SATB1 expression promoted tumor cell glycolysis and glutamine metabolism, while USP47 protein bound to and deubiquitinated SATB1 to increase its intracellular levels, thus promoting glycolysis and glutamine metabolism. USP47 promotion of PTC development may be due to its stabilization of SATB1 protein, suggesting that targeting the USP47/SATB1 signaling axis may serve as a therapeutic intervention for PTC.

Keywords:  Warburg effect; glutamine metabolism; papillary thyroid carcinoma; special AT-rich sequence-binding protein-1; ubiquitin carboxy-terminal hydrolase 47

DOI:  https://doi.org/10.3892/ol.2023.13956
Int J Colorectal Dis. 2023 Aug 11. 38(1): 212

Effects of glutamine on plasma protein and inflammation in postoperative patients with colorectal cancer: a meta-analysis of randomized controlled trials.

Kai Xiong, Guangsong Li, Yu Zhang, Tiantian Bao, Ping Li, Xiangdong Yang, Jiang Chen.

   OBJECTIVE: To evaluate the effects of glutamine on the plasma protein and inflammatory responses in colorectal cancer (CRC) patients following radical surgery.
METHODS: We thoroughly retrieved online databases (EMBASE, MEDLINE, PubMed, and others) and selected the randomized controlled trials (RCTs) with glutamine vs. conventional nutrition or blank treatment up until March 2023. The plasma protein associated markers indicators (consisting of albumin (ALB), prealbumin (PA), nitrogen balance (NB), total protein (TP)), inflammatory indicators (including TNF-α, CRP, infectious complications (ICs)), and matching 95% confidence intervals (CIs) were evaluated utilizing the pooled analysis. Subsequently, meta-regression analysis, contour-enhanced funnel plot, Egger's test, and sensitivity analysis were carried out.
RESULTS: We discovered 26 RCTs, included an aggregate of 1678 patients, out of which 844 were classified into the glutamine group whereas 834 were classified into the control group. The findings recorded from pooled analysis illustrated that glutamine substantially enhanced the plasma protein markers (ALB [SMD[random-effect] = 0.79, 95% CI: 0.55 to 1.03, I2 = 79.4%], PA [SMD[random-effect] = 0.94, 95% CI: 0.69 to 1.20, I2 = 75.1%], NB [SMD[random-effect] = 1.11, 95% CI: 0.46 to 1.75, I2 = 86.9%). However, the content of TP was subjected to comparison across the 2 groups, and no statistical significance was found (SMD[random-effect] = - 0.02, 95% CI: - 0.60 to 0.57, P = 0.959, I2 = 89.7%). Meanwhile, the inflammatory indicators (including TNF-α [SMD[random-effect] = - 1.86, 95% CI: - 2.21 to - 1.59, I2 = 56.7%], CRP [SMD[random-effect] = - 1.94, 95% CI: - 2.41 to - 1.48, I2 = 79.9%], ICs [RR[fixed-effect] = 0.31, 95% CI: 0.21 to 0.46, I2 = 0.00%]) were decreased significantly followed by the treatment of glutamine.
CONCLUSIONS: The current study's findings illustrated that glutamine was an effective pharmaco-nutrient agent in treating CRC patients following a radical surgical operation. PROSPERO registration number: CRD42021243327.

Keywords:  Colorectal cancer; Glutamine; Inflammation; Meta-analysis; Nutritional status

DOI:  https://doi.org/10.1007/s00384-023-04504-8
Cell Metab. 2023 Aug 08. pii: S1550-4131(23)00265-6. [Epub ahead of print]35(8): 1283-1303

Emerging therapies in cancer metabolism.

Yi Xiao, Tian-Jian Yu, Ying Xu, Rui Ding, Yi-Ping Wang, Yi-Zhou Jiang, Zhi-Ming Shao.

Metabolic reprogramming in cancer is not only a biological hallmark but also reveals treatment vulnerabilities. Numerous metabolic molecules have shown promise as treatment targets to impede tumor progression in preclinical studies, with some advancing to clinical trials. However, the intricacy and adaptability of metabolic networks hinder the effectiveness of metabolic therapies. This review summarizes the metabolic targets for cancer treatment and provides an overview of the current status of clinical trials targeting cancer metabolism. Additionally, we decipher crucial factors that limit the efficacy of metabolism-based therapies and propose future directions. With advances in integrating multi-omics, single-cell, and spatial technologies, as well as the ability to track metabolic adaptation more precisely and dynamically, clinicians can personalize metabolic therapies for improved cancer treatment.

DOI: https://doi.org/10.1016/j.cmet.2023.07.006
Cell Mol Life Sci. 2023 Aug 10. 80(9): 244

Breast cancers as ecosystems: a metabolic perspective.

Flavia Martino, Mariadomenica Lupi, Enrico Giraudo, Letizia Lanzetti.

  Breast cancer (BC) is the most frequently diagnosed cancer and one of the major causes of cancer death. Despite enormous progress in its management, both from the therapeutic and early diagnosis viewpoints, still around 700,000 patients succumb to the disease each year, worldwide. Late recurrency is the major problem in BC, with many patients developing distant metastases several years after the successful eradication of the primary tumor. This is linked to the phenomenon of metastatic dormancy, a still mysterious trait of the natural history of BC, and of several other types of cancer, by which metastatic cells remain dormant for long periods of time before becoming reactivated to initiate the clinical metastatic disease. In recent years, it has become clear that cancers are best understood if studied as ecosystems in which the impact of non-cancer-cell-autonomous events-dependent on complex interaction between the cancer and its environment, both local and systemic-plays a paramount role, probably as significant as the cell-autonomous alterations occurring in the cancer cell. In adopting this perspective, a metabolic vision of the cancer ecosystem is bound to improve our understanding of the natural history of cancer, across space and time. In BC, many metabolic pathways are coopted into the cancer ecosystem, to serve the anabolic and energy demands of the cancer. Their study is shedding new light on the most critical aspect of BC management, of metastatic dissemination, and that of the related phenomenon of dormancy and fostering the application of the knowledge to the development of metabolic therapies.

Keywords:  Adipocytes; Glycolysis; Metabolism; Metastasis; Microbiota; Microenvironment

DOI:  https://doi.org/10.1007/s00018-023-04902-9
Cancers (Basel). 2023 Jul 29. pii: 3868. [Epub ahead of print]15(15):

Extracellular Matrix Collagen I Differentially Regulates the Metabolic Plasticity of Pancreatic Ductal Adenocarcinoma Parenchymal Cell and Cancer Stem Cell.

Diana Tavares-Valente, Stefania Cannone, Maria Raffaella Greco, Tiago Miguel Amaral Carvalho, Fátima Baltazar, Odília Queirós, Gennaro Agrimi, Stephan J Reshkin, Rosa Angela Cardone.

  Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of less than 10 percent largely due to the intense fibrotic desmoplastic reaction, characterized by high levels of extracellular matrix (ECM) collagen I that constitutes a niche for a subset of cancer cells, the cancer stem cells (CSCs). Cancer cells undergo a complex metabolic adaptation characterized by changes in metabolic pathways and biosynthetic processes. The use of the 3D organotypic model in this study allowed us to manipulate the ECM constituents and mimic the progression of PDAC from an early tumor to an ever more advanced tumor stage. To understand the role of desmoplasia on the metabolism of PDAC parenchymal (CPC) and CSC populations, we studied their basic metabolic parameters in organotypic cultures of increasing collagen content to mimic in vivo conditions. We further measured the ability of the bioenergetic modulators (BMs), 2-deoxyglucose, dichloroacetate and phenformin, to modify their metabolic dependence and the therapeutic activity of paclitaxel albumin nanoparticles (NAB-PTX). While all the BMs decreased cell viability and increased cell death in all ECM types, a distinct, collagen I-dependent profile was observed in CSCs. As ECM collagen I content increased (e.g., more aggressive conditions), the CSCs switched from glucose to mostly glutamine metabolism. All three BMs synergistically potentiated the cytotoxicity of NAB-PTX in both cell lines, which, in CSCs, was collagen I-dependent and the strongest when treated with phenformin + NAB-PTX. Metabolic disruption in PDAC can be useful both as monotherapy or combined with conventional drugs to more efficiently block tumor growth.

Keywords:  bioenergetic modulators; cancer stem cells; chemoresistance; collagen I; glutamine; pancreatic ductal adenocarcinoma; treatment; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers15153868
Cancers (Basel). 2023 Aug 03. pii: 3942. [Epub ahead of print]15(15):

Cellular Adaptation Takes Advantage of Atavistic Regression Programs during Carcinogenesis.

Davide Gnocchi, Dragana Nikolic, Rosa Rita Paparella, Carlo Sabbà, Antonio Mazzocca.

  Adaptation of cancer cells to extreme microenvironmental conditions (i.e., hypoxia, high acidity, and reduced nutrient availability) contributes to cancer resilience. Furthermore, neoplastic transformation can be envisioned as an extreme adaptive response to tissue damage or chronic injury. The recent Systemic-Evolutionary Theory of the Origin of Cancer (SETOC) hypothesizes that cancer cells "revert" to "primitive" characteristics either ontogenically (embryo-like) or phylogenetically (single-celled organisms). This regression may confer robustness and maintain the disordered state of the tissue, which is a hallmark of malignancy. Changes in cancer cell metabolism during adaptation may also be the consequence of altered microenvironmental conditions, often resulting in a shift toward lactic acid fermentation. However, the mechanisms underlying the robust adaptive capacity of cancer cells remain largely unknown. In recent years, cancer cells' metabolic flexibility has received increasing attention among researchers. Here, we focus on how changes in the microenvironment can affect cancer cell energy production and drug sensitivity. Indeed, changes in the cellular microenvironment may lead to a "shift" toward "atavistic" biologic features, such as the switch from oxidative phosphorylation (OXPHOS) to lactic acid fermentation, which can also sustain drug resistance. Finally, we point out new integrative metabolism-based pharmacological approaches and potential biomarkers for early detection.

Keywords:  cancer drug resistance; tumor adaptation; tumor biology; tumor metabolism

DOI:  https://doi.org/10.3390/cancers15153942
Am J Physiol Cell Physiol. 2023 Aug 07.

Insights into the Tumor-Stromal-Immune Cell Metabolism Crosstalk in Ovarian Cancer.

Priscilla W Tang, Leonard G Frisbie, Nadine Hempel, Lan G Coffman.

  The ovarian cancer tumor microenvironment (TME) consists of a constellation of abundant cellular components, extracellular matrix, and soluble factors. Soluble factors such as cytokines, chemokines, structural proteins, extracellular vesicles, and metabolites are critical means of non-contact cellular communication acting as messengers to convey pro- or anti-tumorigenic signals. Vast advancements have been made in our understanding of how cancer cells adapt their metabolism to meet environmental demands and utilize these adaptations to promote survival, metastasis, and therapeutic resistance. The stromal TME contribution to this metabolic rewiring has been relatively underexplored, particularly in ovarian cancer. Thus, metabolic activity alterations in the TME hold promise for further study and potential therapeutic exploitation. In this review, we focus on the cellular components of the TME with emphasis on: 1) metabolic signatures of ovarian cancer; 2) understanding the stromal cell network and their metabolic crosstalk with tumor cells; and 3) how stromal and tumor cell metabolites alter intratumoral immune cell metabolism and function. Together, these elements provide insight into the metabolic influence of the TME and emphasize the importance of understanding how metabolic performance drives cancer progression.

Keywords:  Ovarian cancer; metabolomics; stroma; tumor microenvironment

DOI:  https://doi.org/10.1152/ajpcell.00588.2022
Int J Mol Sci. 2023 Jul 26. pii: 11969. [Epub ahead of print]24(15):

Glucose Deprivation Induces Cancer Cell Death through Failure of ROS Regulation.

Mingyu Kang, Joon H Kang, In A Sim, Do Y Seong, Suji Han, Hyonchol Jang, Ho Lee, Sang W Kang, Soo-Youl Kim.

  In previous work, we showed that cancer cells do not depend on glycolysis for ATP production, but they do on fatty acid oxidation. However, we found some cancer cells induced cell death after glucose deprivation along with a decrease of ATP production. We investigated the different response of glucose deprivation with two types of cancer cells including glucose insensitive cancer cells (GIC) which do not change ATP levels, and glucose sensitive cancer cells (GSC) which decrease ATP production in 24 h. Glucose deprivation-induced cell death in GSC by more than twofold after 12 h and by up to tenfold after 24 h accompanied by decreased ATP production to compare to the control (cultured in glucose). Glucose deprivation decreased the levels of metabolic intermediates of the pentose phosphate pathway (PPP) and the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) in both GSC and GIC. However, glucose deprivation increased reactive oxygen species (ROS) only in GSC, suggesting that GIC have a higher tolerance for decreased NADPH than GSC. The twofold higher ratio of reduced/oxidized glutathione (GSH/GSSG) in GIS than in GSC correlates closely with the twofold lower ROS levels under glucose starvation conditions. Treatment with N-acetylcysteine (NAC) as a precursor to the biologic antioxidant glutathione restored ATP production by 70% and reversed cell death caused by glucose deprivation in GSC. The present findings suggest that glucose deprivation-induced cancer cell death is not caused by decreased ATP levels, but rather triggered by a failure of ROS regulation by the antioxidant system. Conclusion is clear that glucose deprivation-induced cell death is independent from ATP depletion-induced cell death.

Keywords:  ROS; cancer metabolism; cell death; glucose deprivation; glycolysis

DOI:  https://doi.org/10.3390/ijms241511969
Cold Spring Harb Perspect Med. 2023 Aug 08. pii: a041530. [Epub ahead of print]

Cancer Metabolism Historical Perspectives: A Chronicle of Controversies and Consensus.

Chi V Dang.

A century ago, Otto Warburg's work sparked the field of cancer metabolism, which has since taken a tortuous path. As evidence accumulated over the decades, consensus views of causes of cancer emerged, whereby genetic and epigenetic oncogenic drivers promoted immune evasion and induced new blood vessels and neoplastic metabolism to support tumor growth. Neoplastic cells abandon social cues of intercellular cooperation, escape tissue confinement, metastasize, and ultimately kill the host. Herein, key milestones in the study of cancer metabolism are chronicled with an emphasis on carbohydrate metabolism. The field began with a cancer cell-autonomous view that has been refined by a richer understanding of solid cancers as growing, immune-suppressive, complex organs comprising different cell types that are nourished by a variety of nutrients and variable amounts of oxygen through abnormal neovasculatures. Based on foundational historical studies, our current understanding of cancer metabolism offers a hopeful outlook for targeting metabolism to enhance cancer therapy.

DOI: https://doi.org/10.1101/cshperspect.a041530
Int J Mol Sci. 2023 Jul 26. pii: 11935. [Epub ahead of print]24(15):

Amino Acid Metabolism and Disease.

María Ángeles Pajares.

The origin of life is still a matter of debate, and several hypotheses have been proposed to explain how the building blocks leading to the minimal cell were formed [...].

DOI: https://doi.org/10.3390/ijms241511935