scholarly journals Suppression of the HBP Function Increases Pancreatic Cancer Cell Sensitivity to a Pan-RAS Inhibitor

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 431
Author(s):  
Francesca Ricciardiello ◽  
Laura Bergamaschi ◽  
Humberto De Vitto ◽  
Yang Gang ◽  
Taiping Zhang ◽  
...  
Keyword(s):  
Biosynthetic Pathway ◽  
Pancreatic Cancer Cell ◽  
Combined Treatment ◽  
Cancer Development ◽  
Ductal Adenocarcinoma ◽  
Wild Type ◽  
Novel Therapy ◽  
Hexosamine Biosynthetic Pathway ◽  
Oncogenic Ras ◽  
Negative Effect

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related death and the search for a resolutive therapy is still a challenge. Since KRAS is commonly mutated in PDAC and is one of the main drivers of PDAC progression, its inhibition should be a key strategy for treatment, especially considering the recent development of specific KRAS inhibitors. Nevertheless, the effects of KRAS inhibition can be increased through the co-inhibition of other nodes important for cancer development. One of them could be the hexosamine biosynthetic pathway (HBP), whose enhancement is considered fundamental for PDAC. Here, we demonstrate that PDAC cells expressing oncogenic KRAS, owing to an increase in the HBP flux, become strongly reliant on HBP for both proliferation and survival. In particular, upon treatment with two different compounds, 2-deoxyglucose and FR054, inhibiting both HBP and protein N-glycosylation, these cells undergo apoptosis significantly more than PDAC cells expressing wild-type KRAS. Importantly, we also show that the combined treatment between FR054 and the pan-RAS inhibitor BI-2852 has an additive negative effect on cell proliferation and survival by means of the suppression of both Akt activity and cyclin D1 expression. Thus, co-inhibition of HBP and oncogenic RAS may represent a novel therapy for PDAC patients.

scholarly journals Roles of the hexosamine biosynthetic pathway and pentose phosphate pathway in bile acid‐induced cancer development

2019 ◽  
Vol 110 (8) ◽  
pp. 2408-2420 ◽  
Author(s):  
Masayoshi Munemoto ◽  
Ken‐ichi Mukaisho ◽  
Tomoharu Miyashita ◽  
Katsunobu Oyama ◽  
Yusuke Haba ◽  
...  
Keyword(s):  
Bile Acid ◽  
Pentose Phosphate Pathway ◽  
Biosynthetic Pathway ◽  
Pentose Phosphate ◽  
Cancer Development ◽  
Hexosamine Biosynthetic Pathway

scholarly journals Hyaluronic Acid Fuels Pancreatic Cancer Growth

2020 ◽  
Author(s):  
Peter K. Kim ◽  
Christopher J. Halbrook ◽  
Samuel A. Kerk ◽  
Stephanie Wisner ◽  
Daniel M. Kremer ◽  
...  
Keyword(s):  
Hyaluronic Acid ◽  
Biosynthetic Pathway ◽  
Pancreatic Tumors ◽  
Wild Type ◽  
Salvage Pathway ◽  
Hexosamine Biosynthetic Pathway ◽  
Carbohydrate Polymer ◽  
Rate Limiting ◽  
Proliferation In Vitro

AbstractRewired metabolism is a hallmark of pancreatic ductal adenocarcinomas (PDA). Previously, we demonstrated that PDA cells enhance glycosylation precursor biogenesis through the hexosamine biosynthetic pathway (HBP) via activation of the rate limiting enzyme, glutamine-fructose 6-phosphate amidotransferase 1 (GFAT1). Here, we genetically ablated GFAT1 in PDA cell lines, which completely blocked proliferation in vitro and led to cell death. In contrast, GFAT1 knockout did not impair tumor growth, suggesting that cancer cells can maintain fidelity of glycosylation precursor pools by scavenging nutrients from the tumor microenvironment. Here, we show that hyaluronic acid (HA), an abundant carbohydrate polymer in pancreatic tumors composed of repeating N-acetyl-glucosamine (GlcNAc) and glucuronic acid sugars, can bypass GFAT1 to refuel the HBP via the GlcNAc salvage pathway. Furthermore, HA facilitates proliferation in nutrient-starved wild-type PDA. Together, these data show HA can serve as a nutrient fueling PDA metabolism beyond its previously appreciated structural and signaling roles.

Abstract 524: Phosphofructokinase Coordinates Anabolic Pathways in the Heart

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Kyle L Fulghum ◽  
Pawel K Lorkiewicz ◽  
Teresa Cassel ◽  
Teresa M Fan ◽  
Steven P Jones ◽  
...  
Keyword(s):  
Cardiac Remodeling ◽  
Biosynthetic Pathway ◽  
Energy Charge ◽  
Biosynthetic Pathways ◽  
Wild Type ◽  
Hexosamine Biosynthetic Pathway ◽  
Cardiac Health ◽  
Elevated Activity ◽  
Metabolite Abundance

Energy provision and biosynthesis are thought to be controlled by amphibolic enzymes such as phosphofructokinase (PFK). Nevertheless, it remains unclear how PFK influences collateral biosynthetic pathways in the heart. Here, we investigated the control exerted by PFK on anabolic pathways in the heart using in vivo deep network tracing. Wild-type (WT) mice and mice overexpressing kinase- or phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase transgenes, termed respectively Glyco Lo or Glyco Hi mice, were fed a liquid diet containing 13 C 6 -glucose for 18 h. From freeze-clamped hearts, metabolite abundance and 13 C enrichment were then assessed by ion chromatography-mass spectrometry. Compared with Glyco Hi and WT hearts, Glyco Lo hearts had remarkably higher levels and 13 C enrichment of glucose 6-phosphate, fructose 6-phosphate (F6P) (p<0.01 each, n =4/gp), and purine and pyrimidine biosynthetic pathway intermediates. In addition to elevated activity of nucleotide biosynthetic pathways, we also found in Glyco Lo hearts higher 13 C-hexose incorporation into N-acetyl-D-glucosamine 6-phosphate (p<0.05); however, the levels of UDP-GlcNAc and its enrichment with 13 C were not different between the groups, which suggests that PFK activity influences the hexosamine biosynthetic pathway primarily by modulating F6P incorporation. Whereas Glyco Lo hearts showed lower 13 C fractional enrichment in triacylglycerols and hexosyl ceramide species, Glyco Hi hearts showed higher 13 C fractional enrichment in ceramide species. Interestingly, Glyco Lo hearts had 2-fold lower levels of alpha-ketoglutarate with concomitant increases in glutamate abundance. Energy charge values ranged from 0.69-0.81 with no differences observed between groups.These results suggest that PFK regulates lipid biosynthesis and collateral biosynthetic pathways of glucose metabolism in the heart. Understanding how these pathways contribute to cardiac remodeling could be important for developing metabolic therapies to improve cardiac health.

Metabolic Regulation of Hippocampal Neuronal Development and Its Inhibition After Irradiation

2021 ◽  
Vol 80 (5) ◽  
pp. 467-475
Author(s):  
Yu-Qing Li ◽  
C Shun Wong
Keyword(s):  
Cell Fate ◽  
Metabolic Regulation ◽  
Energy Homeostasis ◽  
Neuronal Development ◽  
Adenosine Monophosphate ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Wild Type ◽  
Newborn Neuron ◽  
Negative Effect

Abstract 5′-Adenosine monophosphate-activated protein kinase (AMPK), a key regulator of cellular energy homeostasis, plays a role in cell fate determination. Whether AMPK regulates hippocampal neuronal development remains unclear. Hippocampal neurogenesis is abrogated after DNA damage. Here, we asked whether AMPK regulates adult hippocampal neurogenesis and its inhibition following irradiation. Adult Cre-lox mice deficient in AMPK in brain, and wild-type mice were used in a birth-dating study using bromodeoxyuridine to evaluate hippocampal neurogenesis. There was no evidence of AMPK or phospho-AMPK immunoreactivity in hippocampus. Increase in p-AMPK but not AMPK expression was observed in granule neurons and subgranular neuroprogenitor cells (NPCs) in the dentate gyrus within 24 hours and persisted up to 9 weeks after irradiation. AMPK deficiency in Cre-lox mice did not alter neuroblast and newborn neuron numbers but resulted in decreased newborn and proliferating NPCs. Inhibition of neurogenesis was observed after irradiation regardless of genotypes. In Cre-lox mice, there was further loss of newborn early NPCs and neuroblasts but not newborn neurons after irradiation compared with wild-type mice. These results are consistent with differential negative effect of AMPK on hippocampal neuronal development and its inhibition after irradiation.

scholarly journals The Negative Effect of Protein Phosphatase Z1 Deletion on the Oxidative Stress Tolerance of Candida albicans Is Synergistic with Betamethasone Exposure

2021 ◽  
Vol 7 (7) ◽  
pp. 540
Author(s):  
Ágnes Jakab ◽  
Tamás Emri ◽  
Kinga Csillag ◽  
Anita Szabó ◽  
Fruzsina Nagy ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Candida Albicans ◽  
Protein Phosphatase ◽  
Combined Treatment ◽  
Specific Protein ◽  
Ergosterol Biosynthesis ◽  
Acid Oxidation ◽  
Menadione Sodium Bisulfite ◽  
Rnaseq Data ◽  
Negative Effect

The glucocorticoid betamethasone (BM) has potent anti-inflammatory and immunosuppressive effects; however, it increases the susceptibility of patients to superficial Candida infections. Previously we found that this disadvantageous side effect can be counteracted by menadione sodium bisulfite (MSB) induced oxidative stress treatment. The fungus specific protein phosphatase Z1 (CaPpz1) has a pivotal role in oxidative stress response of Candida albicans and was proposed as a potential antifungal drug target. The aim of this study was to investigate the combined effects of CaPPZ1 gene deletion and MSB treatment in BM pre-treated C. albicans cultures. We found that the combined treatment increased redox imbalance, enhanced the specific activities of antioxidant enzymes, and reduced the growth in cappz1 mutant (KO) strain. RNASeq data demonstrated that the presence of BM markedly elevated the number of differentially expressed genes in the MSB treated KO cultures. Accumulation of reactive oxygen species, increased iron content and fatty acid oxidation, as well as the inhibiting ergosterol biosynthesis and RNA metabolic processes explain, at least in part, the fungistatic effect caused by the combined stress exposure. We suggest that the synergism between MSB treatment and CaPpz1 inhibition could be considered in developing of a novel combinatorial antifungal strategy accompanying steroid therapy.

scholarly journals Sos-mediated cross-activation of wild-type Ras by oncogenic Ras is essential for tumorigenesis

2012 ◽  
Vol 3 (1) ◽  
Author(s):  
Hao-Hsuan Jeng ◽  
Laura J Taylor ◽  
Dafna Bar-Sagi
Keyword(s):  
Wild Type ◽  
Oncogenic Ras

scholarly journals NMR and LC-MS-Based Metabolomics to Study Osmotic Stress in Lignan-Deficient Flax

Molecules ◽  
2021 ◽  
Vol 26 (3) ◽  
pp. 767
Author(s):  
Kamar Hamade ◽  
Ophélie Fliniaux ◽  
Jean-Xavier Fontaine ◽  
Roland Molinié ◽  
Elvis Otogo Nnang ◽  
...  
Keyword(s):  
Stress Response ◽  
Osmotic Stress ◽  
Biosynthetic Pathway ◽  
Potential Role ◽  
Plant Secondary Metabolites ◽  
Wild Type ◽  
Osmotic Stress Response ◽  
Transgenic Flax ◽  
Insight Into

Lignans, phenolic plant secondary metabolites, are derived from the phenylpropanoid biosynthetic pathway. Although, being investigated for their health benefits in terms of antioxidant, antitumor, anti-inflammatory and antiviral properties, the role of these molecules in plants remains incompletely elucidated; a potential role in stress response mechanisms has been, however, proposed. In this study, a non-targeted metabolomic analysis of the roots, stems, and leaves of wild-type and PLR1-RNAi transgenic flax, devoid of (+) secoisolariciresinol diglucoside ((+) SDG)—the main flaxseed lignan, was performed using 1H-NMR and LC-MS, in order to obtain further insight into the involvement of lignan in the response of plant to osmotic stress. Results showed that wild-type and lignan-deficient flax plants have different metabolic responses after being exposed to osmotic stress conditions, but they both showed the capacity to induce an adaptive response to osmotic stress. These findings suggest the indirect involvement of lignans in osmotic stress response.

scholarly journals The Hexosamine Biosynthetic Pathway as a Therapeutic Target after Cartilage Trauma: Modification of Chondrocyte Survival and Metabolism by Glucosamine Derivatives and PUGNAc in an Ex Vivo Model

2021 ◽  
Vol 22 (14) ◽  
pp. 7247
Author(s):  
Jana Riegger ◽  
Julia Baumert ◽  
Frank Zaucke ◽  
Rolf E. Brenner
Keyword(s):  
Biosynthetic Pathway ◽  
Ex Vivo ◽  
Type Ii Collagen ◽  
Cartilage Explants ◽  
Uridine Diphosphate ◽  
Cell Protection ◽  
Ex Vivo Model ◽  
Human Cartilage ◽  
Hexosamine Biosynthetic Pathway ◽  
Cellular Processes

The hexosamine biosynthetic pathway (HBP) is essential for the production of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), the building block of glycosaminoglycans, thus playing a crucial role in cartilage anabolism. Although O-GlcNAcylation represents a protective regulatory mechanism in cellular processes, it has been associated with degenerative diseases, including osteoarthritis (OA). The present study focuses on HBP-related processes as potential therapeutic targets after cartilage trauma. Human cartilage explants were traumatized and treated with GlcNAc or glucosamine sulfate (GS); PUGNAc, an inhibitor of O-GlcNAcase; or azaserine (AZA), an inhibitor of GFAT-1. After 7 days, cell viability and gene expression analysis of anabolic and catabolic markers, as well as HBP-related enzymes, were performed. Moreover, expression of catabolic enzymes and type II collagen (COL2) biosynthesis were determined. Proteoglycan content was assessed after 14 days. Cartilage trauma led to a dysbalanced expression of different HBP-related enzymes, comparable to the situation in highly degenerated tissue. While GlcNAc and PUGNAc resulted in significant cell protection after trauma, only PUGNAc increased COL2 biosynthesis. Moreover, PUGNAc and both glucosamine derivatives had anti-catabolic effects. In contrast, AZA increased catabolic processes. Overall, “fueling” the HBP by means of glucosamine derivatives or inhibition of deglycosylation turned out as cells and chondroprotectives after cartilage trauma.

scholarly journals Carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6) in Pancreatic Ductal Adenocarcinoma (PDA): An integrative analysis of a novel therapeutic target

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Ritu Pandey ◽  
Muhan Zhou ◽  
Shariful Islam ◽  
Baowei Chen ◽  
Natalie K Barker ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Therapeutic Target ◽  
Cell Activity ◽  
Gene Expression Omnibus ◽  
The Cancer Genome Atlas ◽  
Ductal Adenocarcinoma ◽  
Wild Type ◽  
Cancer Genome Atlas ◽  
Novel Therapeutic

AbstractWe investigated biomarker CEACAM6, a highly abundant cell surface adhesion receptor that modulates the extracellular matrix (ECM) in pancreatic ductal adenocarcinoma (PDA). The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) RNA-Seq data from PDA patients were analyzed for CEACAM6 expression and evaluated for overall survival, association, enrichment and correlations. A CRISPR/Cas9 Knockout (KO) of CEACAM6 in PDA cell line for quantitative proteomics, mitochondrial bioenergetics and tumor growth in mice were conducted. We found CEACAM6 is over-expressed in primary and metastatic basal and classical PDA subtypes. Highest levels are in classical activated stroma subtype. CEACAM6 over-expression is universally a poor prognostic marker in KRAS mutant and wild type PDA. High CEACAM6 expression is associated with low cytolytic T-cell activity in both basal and classical PDA subtypes and correlates with low levels of T-REG markers. In HPAF-II cells knockout of CEACAM6 alters ECM-cell adhesion, catabolism, immune environment, transmembrane transport and autophagy. CEACAM6 loss increases mitochondrial basal and maximal respiratory capacity. HPAF-II CEACAM6−/− cells are growth suppressed by >65% vs. wild type in mice bearing tumors. CEACAM6, a key regulator affects several hallmarks of PDA including the fibrotic reaction, immune regulation, energy metabolism and is a novel therapeutic target in PDA.

scholarly journals Hexosamine Biosynthetic Pathway Mutations Cause Neuromuscular Transmission Defect

2011 ◽  
Vol 88 (2) ◽  
pp. 162-172 ◽  
Author(s):  
Jan Senderek ◽  
Juliane S. Müller ◽  
Marina Dusl ◽  
Tim M. Strom ◽  
Velina Guergueltcheva ◽  
...  
Keyword(s):  
Neuromuscular Transmission ◽  
Biosynthetic Pathway ◽  
Hexosamine Biosynthetic Pathway
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