bims-glucam 2023-02-12 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2023–02–12
seventeen papers selected by
Sreeparna Banerjee, Middle East Technical University

Glutamine Metabolism in Cancer Stem Cells: A Complex Liaison in the Tumor Microenvironment.
MYC/glutamine dependency is a therapeutic vulnerability in pancreatic cancer with deoxycytidine kinase inactivation-induced gemcitabine resistance.
CEMIP promotes small cell lung cancer proliferation by activation of glutamine metabolism via FBXW7/c-Myc-dependent axis.
Glutamine synthetase expression rescues human dendritic cell survival in a glutamine-deprived environment.
ERN1 dependent impact of glucose and glutamine deprivations on PBX3, PBXIP1, PAX6, MEIS1, and MEIS2 genes expression in U87 glioma cells.
Glutamine Deprivation Synergizes the Anticancer Effects of Cold Atmospheric Plasma on Esophageal Cancer Cells.
13C-Metabolic flux analysis of 3T3-L1 adipocytes illuminates its core metabolism under hypoxia.
Metabolic reprogramming in colorectal cancer: regulatory networks and therapy.
The helminth derived peptide FhHDM-1 redirects macrophage metabolism towards glutaminolysis to regulate the pro-inflammatory response.
A reduced model of cell metabolism to revisit the glycolysis-OXPHOS relationship in the deregulated tumor microenvironment.
A High-Throughput Sequencing Data-Based Classifier Reveals the Metabolic Heterogeneity of Hepatocellular Carcinoma.
Modulating Glycolysis to Improve Cancer Therapy.
Asparagine and Glutamine Deprivation Alters Ionizing Radiation Response, Migration and Adhesion of a p53null Colorectal Cancer Cell Line.
Cuproptosis: p53-regulated metabolic cell death?
Glucose metabolic reprogramming and its therapeutic potential in obesity-associated endometrial cancer.
Nutrient transporters: connecting cancer metabolism to therapeutic opportunities.
Glutathione-Related Enzymes and Proteins: A Review.

Int J Mol Sci. 2023 Jan 25. pii: 2337. [Epub ahead of print]24(3):

Glutamine Metabolism in Cancer Stem Cells: A Complex Liaison in the Tumor Microenvironment.

Francesco Pacifico, Antonio Leonardi, Elvira Crescenzi.

  In this review we focus on the role of glutamine in control of cancer stem cell (CSC) fate. We first provide an overview of glutamine metabolism, and then summarize relevant studies investigating how glutamine metabolism modulates the CSC compartment, concentrating on solid tumors. We schematically describe how glutamine in CSC contributes to several metabolic pathways, such as redox metabolic pathways, ATP production, non-essential aminoacids and nucleotides biosynthesis, and ammonia production. Furthermore, we show that glutamine metabolism is a key regulator of epigenetic modifications in CSC. Finally, we briefly discuss how cancer-associated fibroblasts, adipocytes, and senescent cells in the tumor microenvironment may indirectly influence CSC fate by modulating glutamine availability. We aim to highlight the complexity of glutamine's role in CSC, which supports our knowledge about metabolic heterogeneity within the CSC population.

Keywords:  adipocytes; cancer stem cells; cancer-associated fibroblasts; glutamine; metabolism; senescent cells; tumor microenvironment

DOI:  https://doi.org/10.3390/ijms24032337
Mol Cancer Res. 2023 Feb 09. pii: MCR-22-0554. [Epub ahead of print]

MYC/glutamine dependency is a therapeutic vulnerability in pancreatic cancer with deoxycytidine kinase inactivation-induced gemcitabine resistance.

Suman Dash, Takeshi Ueda, Akiyoshi Komuro, Hisayuki Amano, Masahiko Honda, Masahito Kawazu, Hitoshi Okada.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most life-threatening malignancies. Although the deoxycytidine analog gemcitabine has been used as the first-line treatment for PDAC, the primary clinical challenge arises because of an eventual acquisition of resistance. Therefore, it is crucial to elucidate the mechanisms underlying gemcitabine resistance to improve treatment efficacy. To investigate potential genes whose inactivation confers gemcitabine resistance, we performed CRISPR knockout library screening. We found that DCK deficiency is the primary mechanism of gemcitabine resistance, and the inactivation of CRYBA2, DMBX1, CROT, and CD36 slightly conferred gemcitabine resistance. In particular, gene expression analysis revealed that DCK-knockout (KO) cells displayed a significant enrichment of genes associated with MYC targets, folate/one-carbon metabolism and glutamine metabolism pathways. Evidently, chemically targeting each of these pathways significantly reduced the survival of DCK KO cells. Moreover, the pathways enriched in DCK KO cells represented a trend similar to those in PDAC cell lines and samples of patients with PDAC with low DCK expression. We further observed that short-term treatment of parental CFPAC-1 cells with gemcitabine induces the expression of several genes, which promote synthesis and transport of glutamine in a dose-dependent manner, which suggests glutamine availability as a potential mechanism of escaping drug toxicity in an initial response for survival. Thus, our findings provide insights into novel therapeutic approaches for gemcitabine-resistant PDAC and emphasize the involvement of glutamine metabolism in drug-tolerant persister cells. Implications: Our study revealed the key pathways involved in gemcitabine resistance in PDAC, thus providing potential therapeutic strategies.

DOI: https://doi.org/10.1158/1541-7786.MCR-22-0554
Biochem Pharmacol. 2023 Feb 04. pii: S0006-2952(23)00037-0. [Epub ahead of print] 115446

CEMIP promotes small cell lung cancer proliferation by activation of glutamine metabolism via FBXW7/c-Myc-dependent axis.

Xiaoxiang Mo, Xiaoju Shen, Xiaocheng Mo, Fei Yu, Weidan Tan, Zhihua Deng, Jingchuan He, Zhuo Luo, Zhiquan Chen, Jie Yang.

  Small cell lung cancer (SCLC) is the most malignant lung cancer with rapid growth and early metastasis, but still lacks effective targeted therapies to improve the prognosis. Here, we demonstrated that a novel oncogenic protein, cell migration inducing hyaluronic binding protein (CEMIP), was robustly overexpressed in SCLC tissues than that in noncancerous tissues and high expression of CEMIP predicted poor outcomes in clinical specimens and in large sample size cohorts from public databases (GEPIA 2 and CPTAC). Liquid chromatography mass spectrometry (LC-MS) and in vitro/in vivo functional assays indicated that CEMIP contributed to the proliferation by increasing glutamine consumption and their metabolites (glutamate and glutathione) levels in SCLC cells. Moreover, the addition of a GLS1 inhibitor CB-839 dramatically reduced CEMIP-induced SCLC cell proliferation. Mechanistically, beyond as a scaffold protein, CEMIP facilitates glutamine-dependent cell proliferation through inhibiting c-Myc ubiquitination and increasing c-Myc stabilization and nuclear accumulation via hindering the interaction between FBXW7 (a E3 ubiquitin ligase) and its target substrate c-Myc. Taken together, our findings reveal a novel oncogenic role of CEMIP in sustaining SCLC growth via FBXW7/c-Myc-dependent axis, and provide new evidence that inhibition of CEMIP might be a potential therapeutic strategy for the treatment of SCLC.

Keywords:  CEMIP; FBXW7/c-Myc aix; Glutamine metabolism; Proliferation; Small cell lung cancer

DOI:  https://doi.org/10.1016/j.bcp.2023.115446
Front Oncol. 2023 ;13 1120194

Glutamine synthetase expression rescues human dendritic cell survival in a glutamine-deprived environment.

Robert Schoeppe, Nathalie Babl, Sonja-Maria Decking, Gabriele Schönhammer, Andreas Siegmund, Christina Bruss, Katja Dettmer, Peter J Oefner, Linus Frick, Anna Weigert, Jonathan Jantsch, Wolfgang Herr, Michael Rehli, Kathrin Renner, Marina Kreutz.

   Introduction: Glutamine deficiency is a well-known feature of the tumor environment. Here we analyzed the impact of glutamine deprivation on human myeloid cell survival and function.
Methods: Different types of myeloid cells were cultured in the absence or presence of glutamine and/or with L-methionine-S-sulfoximine (MSO), an irreversible glutamine synthetase (GS) inhibitor. GS expression was analyzed on mRNA and protein level. GS activity and the conversion of glutamate to glutamine by myeloid cells was followed by 13C tracing analyses.
Results: The absence of extracellular glutamine only slightly affected postmitotic human monocyte to dendritic cell (DC) differentiation, function and survival. Similar results were obtained for monocyte-derived macrophages. In contrast, proliferation of the monocytic leukemia cell line THP-1 was significantly suppressed. While macrophages exhibited high constitutive GS expression, glutamine deprivation induced GS in DC and THP-1. Accordingly, proliferation of THP-1 was rescued by addition of the GS substrate glutamate and 13C tracing analyses revealed conversion of glutamate to glutamine. Supplementation with the GS inhibitor MSO reduced the survival of DC and macrophages and counteracted the proliferation rescue of THP-1 by glutamate.
Discussion: Our results show that GS supports myeloid cell survival in a glutamine poor environment. Notably, in addition to suppressing proliferation and survival of tumor cells, the blockade of GS also targets immune cells such as DCs and macrophages.

Keywords:  dendritic cells; glutamate; glutamine; glutamine synthetase; macrophages

DOI:  https://doi.org/10.3389/fonc.2023.1120194
Endocr Regul. 2023 Jan 01. 57(1): 37-47

ERN1 dependent impact of glucose and glutamine deprivations on PBX3, PBXIP1, PAX6, MEIS1, and MEIS2 genes expression in U87 glioma cells.

Dariia O Krasnytska, Yuliia M Viletska, Dmytro O Minchenko, Olena O Khita, Dariia O Tsymbal, Anastasiia A Cherednychenko, Halyna E Kozynkevych, Nataliia S Oksiom, Oleksandr H Minchenko.

  Objective. Homeobox genes play a fundamental role in the embryogenesis, but some of them have been linked to oncogenesis. The present study is aimed to investigate the impact of glucose and glutamine deprivations on the expression of homeobox genes such as PAX6 (paired box 6), PBX3 (PBX homeobox 3), PBXIP1 (PBX homeobox interacting protein 1), MEIS1 (MEIS homeobox 1), and MEIS2 in ERN1 knockdown U87 glioma cells with the intent to reveal the role of ERN1 (endoplasmic reticulum to nucleus signaling 1) signaling pathway on the endoplasmic reticulum stress dependent regulation of homeobox genes. Methods. The control (transfected by empty vector) and ERN1 knockdown (transfected by dominant-negative ERN1) U87 glioma cells were exposed to glucose and glutamine deprivations for 24 h. The cells RNA was extracted and reverse transcribed. The expression level of PAX6, PBX3, PBXIP1, MEIS1, and MEIS2 genes was evaluated by a real-time quantitative polymerase chain reaction analysis and normalized to ACTB. Results. It was found that glucose deprivation down-regulated the expression level of PAX6, MEIS1, and MEIS2 genes in control glioma cells, but did not significantly alter PBX3 and PBXIP1 genes expression. At the same time, ERN1 knockdown significantly modified the sensitivity of all studied genes to glucose deprivation. Other changes in gene expression were detected in control glioma cells under the glutamine deprivation. The expression of PBX3 and MEIS2 genes was down- while PAX6 and PBXIP1 genes up-regulated. Furthermore, ERN1 knockdown significantly modified the effect of glutamine deprivation on the majority of studied genes expression in U87 glioma cells. Conclusion. The results of the present study demonstrate that the exposure of U87 glioma cells under glucose and glutamine deprivations affected the expression of the majority of the studied homeobox genes and that the sensitivity of PAX6, PBX3, PBXIP1, MEIS1, and MEIS2 genes expression under these experimental conditions is mediated by ERN1, the major pathway of the endoplasmic reticulum stress signaling.

Keywords:  ERN1 knockdown; U87 glioma cells; glucose and glutamine deprivations; homeobox genes; mRNA expression

DOI:  https://doi.org/10.2478/enr-2023-0005
Molecules. 2023 Feb 02. pii: 1461. [Epub ahead of print]28(3):

Glutamine Deprivation Synergizes the Anticancer Effects of Cold Atmospheric Plasma on Esophageal Cancer Cells.

Wei Zhao, Xumiao Jing, Tao Wang, Fengqiu Zhang.

  Esophageal cancer is a highly aggressive malignancy with a low response to standard anti-cancer therapies. There is an unmet need to develop new therapeutic strategies to improve the clinical outcomes of current treatments. Cold atmospheric plasma (CAP) is a promising approach for cancer treatment, and has displayed anticancer efficacy in multiple preclinical models. Recent studies have shown that the efficacy of CAP is positively correlated with intracellular reactive oxygen species (ROS) levels. This suggests that aggressively increasing intracellular ROS levels has the potential to further improve CAP-mediated anticancer efficacy. Glutamine plays an important role in cellular ROS scavenging after being converted to glutathione (GSH, a well-described antioxidant) under physiological conditions, so reducing intracellular glutamine levels seems to be a promising strategy. To test this hypothesis, we treated esophageal cancer cells with CAP while controlling the supply of glutamine. The results showed that glutamine did affect the anticancer effect of CAP, and the combination of CAP stimulation and glutamine deprivation significantly inhibited the proliferation of esophageal cancer cells compared to the control group (p < 0.05). Furthermore, flow cytometric analysis documented a significant increase in more than 10% in apoptosis and necrosis of esophageal cancer cells after this synergistic treatment compared to the control group (p < 0.05). Thus, these results provide the first direct evidence that the biological function of CAP can be modulated by glutamine levels and that combined CAP stimulation and glutamine deprivation represent a promising strategy for the future treatment of esophageal cancer.

Keywords:  cold atmospheric plasma (CAP); esophageal cancer; glutamine deprivation; reactive oxygen species (ROS); synergistic treatment

DOI:  https://doi.org/10.3390/molecules28031461
Metab Eng. 2023 Feb 07. pii: S1096-7176(23)00022-8. [Epub ahead of print]

13C-Metabolic flux analysis of 3T3-L1 adipocytes illuminates its core metabolism under hypoxia.

Eleanor H Oates, Maciek R Antoniewicz.

  Hypoxia has been identified as a major factor in the pathogenesis of adipose tissue inflammation, which is a hallmark of obesity and obesity-linked type 2 diabetes mellitus. In this study, we have investigated the impact of hypoxia (1% oxygen) on the physiology and metabolism of 3T3-L1 adipocytes, a widely used cell culture model of adipose. Specifically, we applied parallel labeling experiments, isotopomer spectral analysis, and 13C-metabolic flux analysis to quantify the impact of hypoxia on adipogenesis, de novo lipogenesis and metabolic flux reprogramming in adipocytes. We found that 3T3-L1 cells can successfully differentiate into lipid-accumulating adipocytes under hypoxia, although the production of lipids was reduced by about 40%. Quantitative flux analysis demonstrated that short-term (1 day) and long-term (7 days) exposure to hypoxia resulted in similar reprogramming of cellular metabolism. Overall, we found that hypoxia: 1) reduced redox and energy generation by more than 2-fold and altered the patterns of metabolic pathway contributions to production and consumption of energy and redox cofactors; 2) redirected glucose metabolism from pentose phosphate pathway and citric acid cycle to lactate production; 3) rewired glutamine metabolism, from net glutamine production to net glutamine catabolism; 4) suppressed branched chain amino acid consumption; and 5) reduced biosynthesis of odd-chain fatty acids and mono-unsaturated fatty acids, while synthesis of saturated even-chain fatty acids was not affected. Together, these results highlight the profound impact of extracellular microenvironment on adipocyte metabolic activity and function.

Keywords:  3T3-L1 cells; Adipocytes; Differentiation; Hypoxia; Metabolism; de novo lipogenesis

DOI:  https://doi.org/10.1016/j.ymben.2023.02.002
Cell Biosci. 2023 Feb 08. 13(1): 25

Metabolic reprogramming in colorectal cancer: regulatory networks and therapy.

Jieping Zhang, Shaomin Zou, Lekun Fang.

  With high prevalence and mortality, together with metabolic reprogramming, colorectal cancer is a leading cause of cancer-related death. Metabolic reprogramming gives tumors the capacity for long-term cell proliferation, making it a distinguishing feature of cancer. Energy and intermediate metabolites produced by metabolic reprogramming fuel the rapid growth of cancer cells. Aberrant metabolic enzyme-mediated tumor metabolism is regulated at multiple levels. Notably, tumor metabolism is affected by nutrient levels, cell interactions, and transcriptional and posttranscriptional regulation. Understanding the crosstalk between metabolic enzymes and colorectal carcinogenesis factors is particularly important to advance research for targeted cancer therapy strategies via the investigation into the aberrant regulation of metabolic pathways. Hence, the abnormal roles and regulation of metabolic enzymes in recent years are reviewed in this paper, which provides an overview of targeted inhibitors for targeting metabolic enzymes in colorectal cancer that have been identified through tumor research or clinical trials.

Keywords:  Colorectal cancer; Metabolic enzymes; Metabolic reprogramming; Signal transduction; Targeted therapy

DOI:  https://doi.org/10.1186/s13578-023-00977-w
Front Immunol. 2023 ;14 1018076

The helminth derived peptide FhHDM-1 redirects macrophage metabolism towards glutaminolysis to regulate the pro-inflammatory response.

Susel Loli Quinteros, Eliana von Krusenstiern, Nathaniel W Snyder, Akane Tanaka, Bronwyn O'Brien, Sheila Donnelly.

  We have previously identified an immune modulating peptide, termed FhHDM-1, within the secretions of the liver fluke, Fasciola hepatica, which is sufficiently potent to prevent the progression of type 1 diabetes and multiple sclerosis in murine models of disease. Here, we have determined that the FhHDM-1 peptide regulates inflammation by reprogramming macrophage metabolism. Specifically, FhHDM-1 switched macrophage metabolism to a dependence on oxidative phosphorylation fuelled by fatty acids and supported by the induction of glutaminolysis. The catabolism of glutamine also resulted in an accumulation of alpha ketoglutarate (α-KG). These changes in metabolic activity were associated with a concomitant reduction in glycolytic flux, and the subsequent decrease in TNF and IL-6 production at the protein level. Interestingly, FhHDM-1 treated macrophages did not express the characteristic genes of an M2 phenotype, thereby indicating the specific regulation of inflammation, as opposed to the induction of an anti-inflammatory phenotype per se. Use of an inactive derivative of FhHDM-1, which did not modulate macrophage responses, revealed that the regulation of immune responses was dependent on the ability of FhHDM-1 to modulate lysosomal pH. These results identify a novel functional association between the lysosome and mitochondrial metabolism in macrophages, and further highlight the significant therapeutic potential of FhHDM-1 to prevent inflammation.

Keywords:  Fasciola hepatica; alpha-ketoglutarate (α-KG); fatty acid oxidation (FAO); glutaminolysis; helminth defence molecule; immune regulation; immunometabolism; macrophage

DOI:  https://doi.org/10.3389/fimmu.2023.1018076
J Theor Biol. 2023 Feb 03. pii: S0022-5193(23)00030-9. [Epub ahead of print] 111434

A reduced model of cell metabolism to revisit the glycolysis-OXPHOS relationship in the deregulated tumor microenvironment.

Pierre Jacquet, Angélique Stéphanou.

  Cancer cells metabolism focuses the interest of the cancer research community. Although this process is intensely studied experimentally, there are very few theoretical models that address this issue. One of the main reasons is the extraordinary complexity of the metabolism that involves numerous interdependent regulatory networks which makes the computational recreation of this complexity illusory. In this study we propose a reduced model of the metabolism which focuses on the interrelation of the three main energy metabolites which are oxygen, glucose and lactate in order to better understand the dynamics of the core system of the glycolysis-OXPHOS relationship. So simple as it is, the model highlights the main rules allowing the cell to dynamically adapt its metabolism to its changing environment. It also makes it possible to address this impact at the tissue scale. The simulations carried out in a spheroid show non-trivial spatial heterogeneity of energy metabolism. It further suggests that the metabolic features that are commonly attributed to cancer cells are not necessarily due to an intrinsic abnormality of the cells. They can emerge spontaneously due to the deregulated over-acidic environment.

Keywords:  Acidity; Energetic needs; Pyruvate-lactate; Theoretical model; Warburg effect

DOI:  https://doi.org/10.1016/j.jtbi.2023.111434
Cancers (Basel). 2023 Jan 18. pii: 592. [Epub ahead of print]15(3):

A High-Throughput Sequencing Data-Based Classifier Reveals the Metabolic Heterogeneity of Hepatocellular Carcinoma.

Maolin Ye, Xuewei Li, Lirong Chen, Shaocong Mo, Jie Liu, Tiansheng Huang, Feifei Luo, Jun Zhang.

  Metabolic heterogeneity plays a key role in poor outcomes in malignant tumors, but its role in hepatocellular carcinoma (HCC) remains largely unknown. In the present study, we aim to disentangle the metabolic heterogeneity features of HCC by developing a classification system based on metabolism pathway activities in high-throughput sequencing datasets. As a result, HCC samples were classified into two distinct clusters: cluster 1 showed high levels of glycolysis and pentose phosphate pathway activity, while cluster 2 exhibited high fatty acid oxidation and glutaminolysis status. This metabolic reprogramming-based classifier was found to be highly correlated with several clinical variables, including overall survival, prognosis, TNM stage, and 𝛼-fetoprotein (AFP) expression. Of note, activated oncogenic pathways, a higher TP53 mutation rate, and increased stemness were also observed in cluster 1, indicating a causal relationship between metabolic reprogramming and carcinogenesis. Subsequently, distinct metabolism-targeted therapeutic strategies were proven in human HCC cell lines, which exhibit the same metabolic properties as corresponding patient samples based on this classification system. Furthermore, the metabolic patterns and effects of different types of cells in the tumor immune microenvironment were explored by referring to both bulk and single-cell data. It was found that malignant cells had the highest overall metabolic activities, which may impair the anti-tumor capacity of CD8+ T cells through metabolic competition, and this provided a potential explanation for why immunosuppressive cells had higher overall metabolic activities than those with anti-tumor functions. Collectively, this study established an HCC classification system based on the gene expression of energy metabolism pathways. Its prognostic and therapeutic value may provide novel insights into personalized clinical practice in patients with metabolic heterogeneity.

Keywords:  hepatocellular carcinoma; metabolic competition; metabolic heterogeneity; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers15030592
Int J Mol Sci. 2023 Jan 30. pii: 2606. [Epub ahead of print]24(3):

Modulating Glycolysis to Improve Cancer Therapy.

Chaithanya Chelakkot, Vipin Shankar Chelakkot, Youngkee Shin, Kyoung Song.

  Cancer cells undergo metabolic reprogramming and switch to a 'glycolysis-dominant' metabolic profile to promote their survival and meet their requirements for energy and macromolecules. This phenomenon, also known as the 'Warburg effect,' provides a survival advantage to the cancer cells and make the tumor environment more pro-cancerous. Additionally, the increased glycolytic dependence also promotes chemo/radio resistance. A similar switch to a glycolytic metabolic profile is also shown by the immune cells in the tumor microenvironment, inducing a competition between the cancer cells and the tumor-infiltrating cells over nutrients. Several recent studies have shown that targeting the enhanced glycolysis in cancer cells is a promising strategy to make them more susceptible to treatment with other conventional treatment modalities, including chemotherapy, radiotherapy, hormonal therapy, immunotherapy, and photodynamic therapy. Although several targeting strategies have been developed and several of them are in different stages of pre-clinical and clinical evaluation, there is still a lack of effective strategies to specifically target cancer cell glycolysis to improve treatment efficacy. Herein, we have reviewed our current understanding of the role of metabolic reprogramming in cancer cells and how targeting this phenomenon could be a potential strategy to improve the efficacy of conventional cancer therapy.

Keywords:  cancer metabolism; combination therapy; glycolysis

DOI:  https://doi.org/10.3390/ijms24032606
Int J Mol Sci. 2023 Feb 03. pii: 2983. [Epub ahead of print]24(3):

Asparagine and Glutamine Deprivation Alters Ionizing Radiation Response, Migration and Adhesion of a p53null Colorectal Cancer Cell Line.

Isabella Guardamagna, Ombretta Iaria, Leonardo Lonati, Alice Mentana, Andrea Previtali, Virginia Uggè, Giovanni Battista Ivaldi, Marco Liotta, Paola Tabarelli de Fatis, Claudia Scotti, Greta Pessino, Maristella Maggi, Giorgio Baiocco.

  Colorectal cancer (CRC) is the most prominent form of colon cancer for both incidence (38.7 per 100,000 people) and mortality (13.9 per 100,000 people). CRC's poor response to standard therapies is linked to its high heterogeneity and complex genetic background. Dysregulation or depletion of the tumor suppressor p53 is involved in CRC transformation and its capability to escape therapy, with p53null cancer subtypes known, in fact, to have a poor prognosis. In such a context, new therapeutic approaches aimed at reducing CRC proliferation must be investigated. In clinical practice, CRC chemotherapy is often combined with radiation therapy with the aim of blocking the expansion of the tumor mass or removing residual cancer cells, though contemporary targeting of amino acid metabolism has not yet been explored. In the present study, we used the p53null Caco-2 model cell line to evaluate the effect of a possible combination of radiation and L-Asparaginase (L-ASNase), a protein drug that blocks cancer proliferation by impairing asparagine and glutamine extracellular supply. When L-ASNase was administered immediately after IR, we observed a reduced proliferative capability, a delay in DNA-damage response and a reduced capability to adhere and migrate. Our data suggest that a correctly timed combination of X-rays and L-ASNase treatment could represent an advantage in CRC therapy.

Keywords:  L-Asparaginase; adhesion; autophagy; colorectal cancer; extracellular matrix; p53; radiotherapy; ɣH2AX

DOI:  https://doi.org/10.3390/ijms24032983
Cell Death Differ. 2023 Feb 08.

Cuproptosis: p53-regulated metabolic cell death?

Chen Xiong, Hong Ling, Qian Hao, Xiang Zhou.

Cuproptosis is a novel type of copper-induced cell death that primarily occurs in cells that utilize oxidative phosphorylation as the main metabolic pathway to produce energy. Copper directly associates with the lipoylated proteins of the tricarboxylic acid cycle, leading to the disulfide-bond-dependent aggregation of these lipoylated proteins, destabilization of the iron-sulfur cluster proteins, and consequent proteotoxic stress. Cancer cells prefer glycolysis (Warburg effect) to oxidative phosphorylation for producing intermediate metabolites and energy, thereby achieving resistance to cuproptosis. Interestingly, the tumor suppressor p53 is a crucial metabolic regulator that inhibits glycolysis and drives a metabolic switch towards oxidative phosphorylation in cancer cells. Additionally, p53 regulates the biogenesis of iron-sulfur clusters and the copper chelator glutathione, which are two critical components of the cuproptotic pathway, suggesting that this tumor suppressor might play a role in cuproptosis. Furthermore, the possible roles of mutant p53 in regulating cuproptosis are discussed. In this essay, we review the recent progress in the understanding of the mechanism underlying cuproptosis, revisit the roles of p53 in metabolic regulation and iron-sulfur cluster and glutathione biosynthesis, and propose several potential mechanisms for wild-type and mutant p53-mediated cuproptosis regulation.

DOI: https://doi.org/10.1038/s41418-023-01125-0
J Transl Med. 2023 Feb 07. 21(1): 94

Glucose metabolic reprogramming and its therapeutic potential in obesity-associated endometrial cancer.

Pengzhu Huang, Xiangqin Fan, Hongfei Yu, Kaiwen Zhang, Huanrong Li, Yingmei Wang, Fengxia Xue.

  Endometrial cancer (EC) is a common gynecological cancer that endangers women health. Although substantial progresses of EC management have been achieved in recent years, the incidence of EC still remains high. Obesity has been a common phenomenon worldwide that increases the risk of EC. However, the mechanism associating obesity and EC has not been fully understood. Metabolic reprogramming as a remarkable characteristic of EC is currently emerging. As the primary factor of metabolic syndrome, obesity promotes insulin resistance, hyperinsulinemia and hyperglycaemia. This metabolic disorder remodels systemic status, which increases EC risk and is related with poor prognosis. Glucose metabolism in EC cells is complex and mediated by glycolysis and mitochondria to ensure energy requirement. Factors that affect glucose metabolism may have an impact on EC initiation and progression. In this study, we review the glucose metabolic reprogramming of EC not only systemic metabolism but also inherent tumor cell metabolism. In particular, the role of glucose metabolic regulation in malignant properties of EC will be focused. Understanding of metabolic profile and glucose metabolism-associated regulation mechanism in EC may provide novel perspective for treatment.

Keywords:  Endometrial cancer; Glucose metabolic reprogramming; Glycolysis; Metabolic syndrome; Mitochondria

DOI:  https://doi.org/10.1186/s12967-022-03851-4
Oncogene. 2023 Feb 04.

Nutrient transporters: connecting cancer metabolism to therapeutic opportunities.

Zeribe Chike Nwosu, Mun Gu Song, Marina Pasca di Magliano, Costas A Lyssiotis, Sung Eun Kim.

Cancer cells rely on certain extracellular nutrients to sustain their metabolism and growth. Solute carrier (SLC) transporters enable cells to acquire extracellular nutrients or shuttle intracellular nutrients across organelles. However, the function of many SLC transporters in cancer is unknown. Determining the key SLC transporters promoting cancer growth could reveal important therapeutic opportunities. Here we summarize recent findings and knowledge gaps on SLC transporters in cancer. We highlight existing inhibitors for studying these transporters, clinical trials on treating cancer by blocking transporters, and compensatory transporters used by cancer cells to evade treatment. We propose targeting transporters simultaneously or in combination with targeted therapy or immunotherapy as alternative strategies for effective cancer therapy.

DOI: https://doi.org/10.1038/s41388-023-02593-x
Molecules. 2023 Feb 02. pii: 1447. [Epub ahead of print]28(3):

Glutathione-Related Enzymes and Proteins: A Review.

Janka Vašková, Ladislav Kočan, Ladislav Vaško, Pál Perjési.

  The tripeptide glutathione is found in all eukaryotic cells, and due to the compartmentalization of biochemical processes, its synthesis takes place exclusively in the cytosol. At the same time, its functions depend on its transport to/from organelles and interorgan transport, in which the liver plays a central role. Glutathione is determined as a marker of the redox state in many diseases, aging processes, and cell death resulting from its properties and reactivity. It also uses other enzymes and proteins, which enables it to engage and regulate various cell functions. This paper approximates the role of these systems in redox and detoxification reactions such as conjugation reactions of glutathione-S-transferases, glyoxylases, reduction of peroxides through thiol peroxidases (glutathione peroxidases, peroxiredoxins) and thiol-disulfide exchange reactions catalyzed by glutaredoxins.

Keywords:  cell; glutathione; glutathione enzyme; glutathione system; glutathionylation; redox homeostasis

DOI:  https://doi.org/10.3390/molecules28031447