scholarly journals FSMP-01. ID1 MEDIATES ONE-CARBON MEDIATED PURINE SYNTHESIS IN GLIOBLASTOMA

2021 ◽  
Vol 3 (Supplement_1) ◽  
pp. i16-i16
Author(s):  
Kimia Ghannad-Zadeh ◽  
Megan Wu ◽  
Taylor Wilson ◽  
Robert Flick ◽  
Sunit Das
Keyword(s):  
De Novo ◽  
Regulatory Protein ◽  
Metabolic Reprogramming ◽  
Glioblastoma Cells ◽  
Self Renewal ◽  
Purine Synthesis ◽  
Glioma Initiating Cells ◽  
Effective Combination ◽  
Transcriptional Regulatory ◽  
One Carbon Metabolism

Abstract Inhibitor of DNA-binding-1 (ID1) is a transcriptional regulatory protein involved in maintenance of self-renewal and inhibition of differentiation, and acts as a key regulator of tumorigenesis in glioblastoma. Studies suggest that de novo purine synthesis is essential for the maintenance of rapid proliferation rates in glioma initiating cells. We hypothesise that ID1 plays a role in reprogramming one-carbon mediated de novo purine synthesis, thereby metabolically contributing to the tumorigenic advantage seen in ID1-high glioblastoma cells. The effect of ID1 regulation on metabolic reprogramming of glioblastoma was studied using ID1-knockout U251 glioblastoma cell lines. Protein expression analysis and liquid chromatography mass-spectrometry were respectively used to assess expression and concentration of metabolic enzymes and intermediates of one-carbon and de novo purine synthesis pathways. CD44 expression was analyzed as a marker of cancer stem cells. The expression of DHFR and MTHFD2 was significantly decreased after ID1 knockout. Furthermore, PAICS expression, and overall concentration of IMP, AMP, GMP, and ATP were reduced after ID1 knockout. ID1 expression in glioblastoma tumor xenografts was associated with positive expression of one-carbon metabolism and purine synthesis enzymes, while ID1-/- cells within the same xenograft had significantly reduced expression of these enzymes. The expression of CD44 was reduced after ID1 knockout. This data suggests that ID1 mediates an increase in one-carbon mediated de novo purine synthesis, thereby regulating metabolic reprogramming in glioblastoma cells. The correlation between CD44 and ID1 expression provides further support that ID1 maintains a less differentiated phenotype in a subset of glioblastoma cells, and metabolic reprogramming is one of the mechanisms through which this phenotype, and the capacity for self-renewal are maintained. Further elucidation of the mechanisms through which ID1 mediates metabolic reprograming of glioblastoma cells can lead to developing effective combination therapies coupling chemotherapeutic strategies with targeting of metabolic programs used by cancer initiating cells.

Untangling the Metabolic Reprogramming in Brain Cancer: Discovering Key Molecular Players Using Mass Spectrometry

2019 ◽  
Vol 19 (17) ◽  
pp. 1521-1534 ◽  
Author(s):  
Anatoly Sorokin ◽  
Vsevolod Shurkhay ◽  
Stanislav Pekov ◽  
Evgeny Zhvansky ◽  
Daniil Ivanov ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Brain Cancer ◽  
De Novo ◽  
Aerobic Glycolysis ◽  
Lipid Production ◽  
Dietary Fatty Acids ◽  
Metabolic Reprogramming ◽  
Detection Methods ◽  
Malignant Cells ◽  
Proliferating Cells

Cells metabolism alteration is the new hallmark of cancer, as well as an important method for carcinogenesis investigation. It is well known that the malignant cells switch to aerobic glycolysis pathway occurring also in healthy proliferating cells. Recently, it was shown that in malignant cells de novo synthesis of the intracellular fatty acid replaces dietary fatty acids which change the lipid composition of cancer cells noticeably. These alterations in energy metabolism and structural lipid production explain the high proliferation rate of malignant tissues. However, metabolic reprogramming affects not only lipid metabolism but many of the metabolic pathways in the cell. 2-hydroxyglutarate was considered as cancer cell biomarker and its presence is associated with oxidative stress influencing the mitochondria functions. Among the variety of metabolite detection methods, mass spectrometry stands out as the most effective method for simultaneous identification and quantification of the metabolites. As the metabolic reprogramming is tightly connected with epigenetics and signaling modifications, the evaluation of metabolite alterations in cells is a promising approach to investigate the carcinogenesis which is necessary for improving current diagnostic capabilities and therapeutic capabilities. In this paper, we overview recent studies on metabolic alteration and oncometabolites, especially concerning brain cancer and mass spectrometry approaches which are now in use for the investigation of the metabolic pathway.

scholarly journals Phytochemicals Block Glucose Utilization and Lipid Synthesis to Counteract Metabolic Reprogramming in Cancer Cells

2021 ◽  
Vol 11 (3) ◽  
pp. 1259
Author(s):  
Qiong Wu ◽  
Bo Zhao ◽  
Guangchao Sui ◽  
Jinming Shi
Keyword(s):  
Cancer Cells ◽  
Metabolic Pathways ◽  
De Novo ◽  
Aerobic Glycolysis ◽  
Structural Characteristics ◽  
Natural Compounds ◽  
Metabolic Reprogramming ◽  
De Novo Lipogenesis ◽  
Anticancer Activities ◽  
Substrate Analogs

Aberrant metabolism is one of the hallmarks of cancers. The contributions of dysregulated metabolism to cancer development, such as tumor cell survival, metastasis and drug resistance, have been extensively characterized. “Reprogrammed” metabolic pathways in cancer cells are mainly represented by excessive glucose consumption and hyperactive de novo lipogenesis. Natural compounds with anticancer activities are constantly being demonstrated to target metabolic processes, such as glucose transport, aerobic glycolysis, fatty acid synthesis and desaturation. However, their molecular targets and underlying anticancer mechanisms remain largely unclear or controversial. Mounting evidence indicated that these natural compounds could modulate the expression of key regulatory enzymes in various metabolic pathways at transcriptional and translational levels. Meanwhile, natural compounds could also inhibit the activities of these enzymes by acting as substrate analogs or altering their protein conformations. The actions of natural compounds in the crosstalk between metabolism modulation and cancer cell destiny have become increasingly attractive. In this review, we summarize the activities of natural small molecules in inhibiting key enzymes of metabolic pathways. We illustrate the structural characteristics of these compounds at the molecular level as either inhibitor of various enzymes or regulators of metabolic pathways in cancer cells. Our ultimate goal is to both facilitate the clinical application of natural compounds in cancer therapies and promote the development of novel anticancer therapeutics.

scholarly journals A new folate antimetabolite, 5,10-dideaza-5,6,7,8-tetrahydrofolate is a potent inhibitor of de novo purine synthesis

1989 ◽  
Vol 264 (1) ◽  
pp. 328-333 ◽  
Author(s):  
G P Beardsley ◽  
B A Moroson ◽  
E C Taylor ◽  
R G Moran
Keyword(s):  
De Novo ◽  
Potent Inhibitor ◽  
Purine Synthesis

scholarly journals STEM-29. THE HISTONE VARIANT macroH2A2 ORCHESTRATES AN ACTIONABLE CHROMATIN PROGRAM OF STEMNESS IN GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii202-ii202
Author(s):  
Ana Nikolic ◽  
Anna Bobyn ◽  
Katrina Ellestad ◽  
Xueqing Lun ◽  
Michael Johnston ◽  
...  
Keyword(s):  
Chromatin Accessibility ◽  
Histone Variant ◽  
Clinical Settings ◽  
Glioblastoma Cells ◽  
Self Renewal ◽  
Viral Mimicry ◽  
Experimental Findings ◽  
Preclinical Work

Abstract Glioblastoma cells with the crucial stemness property of self-renewal constitute therapy-resistant reservoirs that seed tumor relapse. Effective targeting of these cells in clinical settings has been hampered by their relative quiescence, which invalidates the cell replication bias of most current treatments. Furthermore, although their dependence on specific chromatin and transcriptional states for the maintenance of stemness programs has been proposed as a vulnerability, these nuclear programs have been challenging to target pharmaceutically. Therefore the identification of targetable chromatin paradigms regulating self-renewal would represent a significant advancement for this incurable malignancy. Here we report a new role for the histone variant macroH2A2 in modulating a targetable epigenetic network of stemness in glioblastoma. By integrating transcriptomic, bulk and single-cell epigenomic datasets we generated from patient-derived models and surgical specimens, we show that macroH2A2 represses a transcriptional network of stemness through direct regulation of chromatin accessibility at enhancer elements. Functional assays in vitro and in vivo further showcase that macroH2A2 antagonizes self-renewal and stemness in glioblastoma preclinical models. In agreement with our experimental findings, high expression of macroH2A2 is a positive prognostic factor in clinical glioblastoma cohorts. Reasoning that increasing macroH2A2 levels could be an effective strategy to repress stemness programs and ameliorate patient outcome, we embarked on a screen to identify compounds that could elevate macroH2A2 levels. We report that an inhibitor of the chromatin remodeler Menin increases macroH2A2 levels, which in turn repress self-renewal. Additionally, we provide evidence that Menin inhibition induces viral mimicry programs and the demise of glioblastoma cells. Menin inhibition is being tested in clinical trials for blood malignancies (NCT04067336). Our preclinical work therefore reveals a novel and central role for macroH2A2 in an epigenetic network of stemness and suggests new clinical approaches for glioblastoma.

scholarly journals Serine synthesis pathway inhibition cooperates with dietary serine and glycine limitation for cancer therapy

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Mylène Tajan ◽  
Marc Hennequart ◽  
Eric C. Cheung ◽  
Fabio Zani ◽  
Andreas K. Hock ◽  
...  
Keyword(s):  
Therapeutic Efficacy ◽  
De Novo ◽  
Carbon Availability ◽  
Global Protein Synthesis ◽  
Enhanced Expression ◽  
One Carbon Metabolism ◽  
Amino Acid Depletion ◽  
Pathway Inhibition

AbstractMany tumour cells show dependence on exogenous serine and dietary serine and glycine starvation can inhibit the growth of these cancers and extend survival in mice. However, numerous mechanisms promote resistance to this therapeutic approach, including enhanced expression of the de novo serine synthesis pathway (SSP) enzymes or activation of oncogenes that drive enhanced serine synthesis. Here we show that inhibition of PHGDH, the first step in the SSP, cooperates with serine and glycine depletion to inhibit one-carbon metabolism and cancer growth. In vitro, inhibition of PHGDH combined with serine starvation leads to a defect in global protein synthesis, which blocks the activation of an ATF-4 response and more broadly impacts the protective stress response to amino acid depletion. In vivo, the combination of diet and inhibitor shows therapeutic efficacy against tumours that are resistant to diet or drug alone, with evidence of reduced one-carbon availability. However, the defect in ATF4-response seen in vitro following complete depletion of available serine is not seen in mice, where dietary serine and glycine depletion and treatment with the PHGDH inhibitor lower but do not eliminate serine. Our results indicate that inhibition of PHGDH will augment the therapeutic efficacy of a serine depleted diet.

scholarly journals Integrin αvβ3 Engagement Regulates Glucose Metabolism and Migration through Focal Adhesion Kinase (FAK) and Protein Arginine Methyltransferase 5 (PRMT5) in Glioblastoma Cells

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1111
Author(s):  
Pulin Che ◽  
Lei Yu ◽  
Gregory K. Friedman ◽  
Meimei Wang ◽  
Xiaoxue Ke ◽  
...  
Keyword(s):  
Oxidative Phosphorylation ◽  
Focal Adhesion ◽  
Aerobic Glycolysis ◽  
Integrin Αvβ3 ◽  
Metabolic Reprogramming ◽  
Migration And Invasion ◽  
Metabolic Shift ◽  
Mitochondrial Oxidative Phosphorylation ◽  
Glioblastoma Cells ◽  
Arginine Methyltransferase

Metabolic reprogramming promotes glioblastoma cell migration and invasion. Integrin αvβ3 is one of the major integrin family members in glioblastoma multiforme cell surface mediating interactions with extracellular matrix proteins that are important for glioblastoma progression. The role of αvβ3 integrin in regulating metabolic reprogramming and its mechanism of action have not been determined in glioblastoma cells. Integrin αvβ3 engagement with osteopontin promotes glucose uptake and aerobic glycolysis, while inhibiting mitochondrial oxidative phosphorylation. Blocking or downregulation of integrin αvβ3 inhibits glucose uptake and aerobic glycolysis and promotes mitochondrial oxidative phosphorylation, resulting in decreased migration and growth in glioblastoma cells. Pharmacological inhibition of focal adhesion kinase (FAK) or downregulation of protein arginine methyltransferase 5 (PRMT5) blocks metabolic shift toward glycolysis and inhibits glioblastoma cell migration and invasion. These results support that integrin αvβ3 and osteopontin engagement plays an important role in promoting the metabolic shift toward glycolysis and inhibiting mitochondria oxidative phosphorylation in glioblastoma cells. The metabolic shift in cell energy metabolism is coupled to changes in migration, invasion, and growth, which are mediated by downstream FAK and PRMT5 in glioblastoma cells.

Pax1 is expressed during development of the thymus epithelium and is required for normal T-cell maturation

Development ◽  
1996 ◽  
Vol 122 (1) ◽  
pp. 23-30 ◽  
Author(s):  
J. Wallin ◽  
H. Eibel ◽  
A. Neubuser ◽  
J. Wilting ◽  
H. Koseki ◽  
...  
Keyword(s):  
T Cell ◽  
Regulatory Protein ◽  
Cell Maturation ◽  
Thymic Epithelial Cells ◽  
Total Size ◽  
Thymic Development ◽  
Transcriptional Regulatory ◽  
Thymus Cells ◽  
T Cell Maturation ◽  
Third Pharyngeal Pouch

Pax1 is a transcriptional regulatory protein expressed during mouse embryogenesis and has been shown to have an important function in vertebral column development. Expression of Pax1 mRNA in the embryonic thymus has been reported previously. Here we show that Pax1 protein expression in thymic epithelial cells can be detected throughout thymic development and in the adult. Expression starts in the early endodermal epithelium lining the foregut region and includes the epithelium of the third pharyngeal pouch, a structure giving rise to part of the thymus epithelium. In early stages of thymus development a large proportion of thymus cells expresses Pax1. With increasing age, the proportion of Pax1-expressing cells is reduced and in the adult mouse only a small fraction of cortical thymic stromal cells retains strong Pax1 expression. Expression of Pax1 in thymus epithelium is necessary for establishing the thymus microenvironment required for normal T cell maturation. Mutations in the Pax-1 gene in undulated mice affect not only the total size of the thymus but also the maturation of thymocytes. The number of thymocytes is reduced about 2- to 5-fold, affecting mainly the CD4+8+ immature and CD4+ mature thymocyte subsets. The expression levels of major thymocyte surface markers remains unchanged with the exception of Thy-1 which was found to be expressed at 3- to 4-fold higher levels.

Sign in / Sign up

Export Citation Format

Share Document