The Nutrient-Sensing Hexosamine Biosynthetic Pathway as the Hub of Cancer Metabolic Rewiring

Chiaradonna, Ferdinando; Ricciardiello, Francesca; Palorini, Roberta

doi:10.3390/cells7060053

Cited by 127 publications

(127 citation statements)

References 227 publications

(297 reference statements)

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“…Part of the glucosamine consumed by cells is incorporated into the hexosamine biosynthetic pathway. The implication of this pathway in the glycosylation of proteins connects the amino sugar in higher organisms to different pathologies ranging from limb and girdle disease 62 to cancer 63 or diabetes 64 . The constructed strain represents a new useful tool to investigate or manipulate the hexosamine biosynthetic pathway in a well characterized model organism.…”

Section: Discussionmentioning

confidence: 99%

Construction and characterization of a Saccharomyces cerevisiae strain able to grow on glucosamine as sole carbon and nitrogen source

Flores

Gancedo

2018

Sci Rep

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Saccharomyces cerevisiae can transport and phosphorylate glucosamine, but cannot grow on this amino sugar. While an enzyme catalyzing the reaction from glucosamine-6-phosphate to fructose-6-phosphate, necessary for glucosamine catabolism, is present in yeasts using N-acetylglucosamine as carbon source, a sequence homology search suggested that such an enzyme is absent from Saccharomyces cerevisiae. The gene YlNAG1 encoding glucosamine-6-phosphate deaminase from Yarrowia lipolytica was introduced into S. cerevisiae and growth in glucosamine tested. The constructed strain grew in glucosamine as only carbon and nitrogen source. Growth on the amino sugar required respiration and caused an important ammonium excretion. Strains overexpressing YlNAG1 and one of the S. cerevisiae glucose transporters HXT1, 2, 3, 4, 6 or 7 grew in glucosamine. The amino sugar caused catabolite repression of different enzymes to a lower extent than that produced by glucose. The availability of a strain of S. cerevisiae able to grow on glucosamine opens new possibilities to investigate or manipulate pathways related with glucosamine metabolism in a well-studied organism.

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Section: Discussionmentioning

confidence: 99%

Construction and characterization of a Saccharomyces cerevisiae strain able to grow on glucosamine as sole carbon and nitrogen source

Flores

Gancedo

2018

Sci Rep

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“…The HBP deviates from glycolysis as a result of the enzyme glutamine fructose‐6‐phosphate aminotransferase (GFAT) (Figure ). About 2% to 5% of the initial glucose that enters glycolysis is routed to enter the HBP, which together with other metabolites including ATP, glutamine and acetyl‐CoA converge to generate UDP‐GlcNAc (Figure ), which is essential for various aspects of signaling controlling differentiation and apoptosis, and also contributes to progression of diseases such as cancer . Thus, the production of UDP‐GlcNAc depends on metabolite availability which can vary in different physiological environments.…”

Section: Direct Control Of Endocytic Membrane Traffic By Metabolitesmentioning

confidence: 99%

Energetic adaptations: Metabolic control of endocytic membrane traffic

Rahmani

Defferrari

Wakarchuk

et al. 2019

Traffic

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Endocytic membrane traffic controls the access of myriad cell surface proteins to the extracellular milieu, and thus gates nutrient uptake, ion homeostasis, signaling, adhesion and migration. Coordination of the regulation of endocytic membrane traffic with a cell's metabolic needs represents an important facet of maintenance of homeostasis under variable conditions of nutrient availability and metabolic demand. Many studies have revealed intimate regulation of endocytic membrane traffic by metabolic cues, from the specific control of certain receptors or transporters, to broader adaptation or remodeling of the endocytic membrane network. We examine how metabolic sensors such as AMP‐activated protein kinase, mechanistic target of rapamycin complex 1 and hypoxia inducible factor 1 determine sufficiency of various metabolites, and in turn modulate cellular functions that includes control of endocytic membrane traffic. We also examine how certain metabolites can directly control endocytic traffic proteins, such as the regulation of specific protein glycosylation by limiting levels of uridine diphosphate N‐acetylglucosamine (UDP‐GlcNAc) produced by the hexosamine biosynthetic pathway. From these ideas emerge a growing appreciation that endocytic membrane traffic is orchestrated by many intrinsic signals derived from cell metabolism, allowing alignment of the functions of cell surface proteins with cellular metabolic requirements. Endocytic membrane traffic determines how cells interact with their environment, thus defining many aspects of nutrient uptake and energy consumption. We examine how intrinsic signals that reflect metabolic status of a cell regulate endocytic traffic of specific proteins, and, in some cases, exert broad control of endocytic membrane traffic phenomena. Hence, endocytic traffic is versatile and adaptable and can be modulated to meet the changing metabolic requirements of a cell.

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“…Interestingly, FBP1 in TN‐E3G3 versus TN‐E0G3 also tends to decrease even though it does not reach statistical significance (data not shown). FBP1 is a pivotal enzyme controlling the exosamine pathway crucial in tumor progression . This observation correlated with a lower level of metabolic proteins typical of ECM3 signature and suggests that a metabolic adaptation is associated to ECM remodeling in ECM3 tumors …”

Section: Discussionmentioning

confidence: 94%

ECM Remodeling in Breast Cancer with Different Grade: Contribution of 2D‐DIGE Proteomics

et al. 2018

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Tumor extracellular matrix (ECM) plays a pivotal role in outcome of breast cancer (BC) patients. Overexpression of 58 genes, encoding 43 structural ECM proteins, has been identified to determine a specific cluster of BC with accelerated metastatic potential only in the undifferentiated (grade III) phenotype. The scope of this study is to characterize protein repertoire able to predict patient outcome in BC according to ECM gene expression pattern and histological grade. The differential proteomic analysis is based on 2D-differential gel electrophoresis, MALDI-MS, bioinformatics, and immunoblotting. Results suggest a relationship among ECM remodeling, signal mechanotransduction, and metabolic rewiring in BCs characterized by a specific mRNA ECM signature and identified a set of dysregulated proteins characteristic of hormone receptors expression as fibrinogen-β chain, collagen α-1(VI) chain, and α-1B-glycoprotein. Furthermore, in triple negative tumors with ECM signature, the FGG and α5β1/αvβ3 integrins increase whereas detyrosinated α-tubulin and mimecan decrease leading to unorganized integrin presentation involving focal adhesion kinase, activation of Rho GTPases associated to epithelial mesenchymal transition. In hormone receptors negative BCs characterized by a specific ECM gene cluster, the differentially regulated proteins, identified in the present study, can be potentially relevant to predict patient's outcome.

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The Nutrient-Sensing Hexosamine Biosynthetic Pathway as the Hub of Cancer Metabolic Rewiring

Cited by 127 publications

References 227 publications

Construction and characterization of a Saccharomyces cerevisiae strain able to grow on glucosamine as sole carbon and nitrogen source

Construction and characterization of a Saccharomyces cerevisiae strain able to grow on glucosamine as sole carbon and nitrogen source

Energetic adaptations: Metabolic control of endocytic membrane traffic

ECM Remodeling in Breast Cancer with Different Grade: Contribution of 2D‐DIGE Proteomics

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