Endoplasmic reticulum stress signals in the tumour and its microenvironment

Nature reviews. Cancer, Journal Year: 2020, Volume and Issue: 21(2), P. 71 - 88

Published: Nov. 19, 2020

Language: Английский

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Revisiting the Warburg effect: historical dogma versus current understanding

The Journal of Physiology, Journal Year: 2020, Volume and Issue: 599(6), P. 1745 - 1757

Published: Dec. 22, 2020

Abstract Contrary to Warburg's original thesis, accelerated aerobic glycolysis is not a primary, permanent and universal consequence of dysfunctional or impaired mitochondria compensating for poor ATP yield per mole glucose. Instead, in most tumours the Warburg effect an essential part ‘selfish’ metabolic reprogramming, which results from interplay between (normoxic/hypoxic) hypoxia‐inducible factor‐1 (HIF‐1) overexpression, oncogene activation (cMyc, Ras), loss function tumour suppressors (mutant p53, mutant phosphatase tensin homologue (PTEN), microRNAs sirtuins with suppressor functions), activated (PI3K–Akt–mTORC1, Ras–Raf–MEK–ERK–cMyc, Jak–Stat3) deactivated (LKB1–AMPK) signalling pathways, components microenvironment, HIF‐1 cooperation epigenetic mechanisms. Molecular functional processes include: (a) considerable acceleration glycolytic fluxes; (b) adequate generation unit time maintain energy homeostasis electrochemical gradients; (c) backup diversion intermediates facilitating biosynthesis nucleotides, non‐essential amino acids, lipids hexosamines; (d) inhibition pyruvate entry into mitochondria; (e) excessive formation accumulation lactate, stimulates growth suppression anti‐tumour immunity – addition, lactate can serve as source normoxic cancer cells drives malignant progression resistances conventional therapies; (f) cytosolic being mainly exported through upregulated lactate–proton symporters (MCT4), working together other H + transporters, carbonic anhydrases (CAII, CAIX), hydrate CO 2 oxidative metabolism form bicarbonate; (g) these proton export mechanisms, concert vascular drainage, responsible extracellular acidification, driving resistance (h) maintenance cellular redox low reactive oxygen species (ROS) formation; (i) p53 PTEN, inhibit mitochondrial biogenesis functions, negatively impacting respiration rate. The switch early event oncogenesis primarily supports cell survival. All all, effect, i.e. presence principle functioning mitochondria, constitutes major driver machinery, therapies, patient outcome. However, evidenced during last two decades, minority primary defects play key role promoting due mutations some Krebs cycle enzymes ROS overproduction. image

Language: Английский

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Acetyl-CoA metabolism in cancer

Nature reviews. Cancer, Journal Year: 2023, Volume and Issue: 23(3), P. 156 - 172

Published: Jan. 19, 2023

Few metabolites can claim a more central and versatile role in cell metabolism than acetyl coenzyme A (acetyl-CoA). Acetyl-CoA is produced during nutrient catabolism to fuel the tricarboxylic acid cycle essential building block for fatty isoprenoid biosynthesis. It also functions as signalling metabolite substrate lysine acetylation reactions, enabling modulation of protein response acetyl-CoA availability. Recent years have seen exciting advances our understanding normal physiology cancer, buoyed by new mouse models, vivo stable-isotope tracing approaches improved methods measuring acetyl-CoA, including specific subcellular compartments. Efforts target metabolic enzymes are advancing, with one therapeutic agent targeting synthesis receiving approval from US Food Drug Administration. In this Review, we give an overview regulation cancer relevance major pathways which participates. We further discuss recent tissues tumours potential these therapeutically. conclude commentary on emerging nodes that may impact biology.

Language: Английский

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Analytical and Biochemical Perspectives of Protein O-GlcNAcylation

Chemical Reviews, Journal Year: 2021, Volume and Issue: 121(3), P. 1513 - 1581

Published: Jan. 8, 2021

Protein O-linked β-N-acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation) is a unique monosaccharide discovered in the early 1980s. With technological advances past several decades, great progress has been made to reveal biochemistry of O-GlcNAcylation, substrates and functional importance protein O-GlcNAcylation. As nutrient sensor, O-GlcNAcylation plays important roles almost all biochemical processes examined. Although proteins extensively reviewed previously, chemical aspects have not fully addressed. In this review, by critically evaluating key publications 35 years, we aim provide comprehensive understanding post-translational (PTM) from analytical perspectives. Specifically, will cover (1) multiple characterization O-GlcNAc cycling components (i.e., substrate donor UDP-GlcNAc, two enzymes transferase O-GlcNAcase, proteins), (2) with variety tools, (3) exploration its modulating chemicals as potential biomarkers therapeutic drugs for diseases. Last but least, discuss challenges possible solutions basic translational research future.

Language: Английский

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Harnessing metabolic dependencies in pancreatic cancers

Nature Reviews Gastroenterology & Hepatology, Journal Year: 2021, Volume and Issue: 18(7), P. 482 - 492

Published: March 19, 2021

Language: Английский

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Metabolic reprogramming in cholangiocarcinoma

Journal of Hepatology, Journal Year: 2022, Volume and Issue: 77(3), P. 849 - 864

Published: May 18, 2022

Language: Английский

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O-GlcNAcylation in cancer development and immunotherapy

Cancer Letters, Journal Year: 2023, Volume and Issue: 566, P. 216258 - 216258

Published: June 4, 2023

Language: Английский

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High dietary fructose promotes hepatocellular carcinoma progression by enhancing O-GlcNAcylation via microbiota-derived acetate

Cell Metabolism, Journal Year: 2023, Volume and Issue: 35(11), P. 1961 - 1975.e6

Published: Oct. 4, 2023

Language: Английский

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Glycosylation: mechanisms, biological functions and clinical implications

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Aug. 5, 2024

Protein post-translational modification (PTM) is a covalent process that occurs in proteins during or after translation through the addition removal of one more functional groups, and has profound effect on protein function. Glycosylation most common PTMs, which polysaccharides are transferred to specific amino acid residues by glycosyltransferases. A growing body evidence suggests glycosylation essential for unfolding various activities organisms, such as playing key role regulation function, cell adhesion immune escape. Aberrant also closely associated with development diseases. Abnormal patterns linked emergence health conditions, including cancer, inflammation, autoimmune disorders, several other However, underlying composition structure glycosylated have not been determined. It imperative fully understand internal differential expression glycosylation, incorporate advanced detection technologies keep knowledge advancing. Investigations clinical applications focused sensitive promising biomarkers, effective small molecule targeted drugs emerging vaccines. These studies provide new area novel therapeutic strategies based glycosylation.

Language: Английский

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O-GlcNAcylation and its role in the immune system

Journal of Biomedical Science, Journal Year: 2020, Volume and Issue: 27(1)

Published: April 29, 2020

O-linked-N-acetylglucosaminylation (O-GlcNAcylation) is a type of glycosylation that occurs when monosaccharide, O-GlcNAc, added onto serine or threonine residues nuclear cytoplasmic proteins by O-GlcNAc transferase (OGT) and which can be reversibly removed O-GlcNAcase (OGA). O-GlcNAcylation couples the processes nutrient sensing, metabolism, signal transduction transcription, plays important roles in development, normal physiology physiopathology. Cumulative studies have indicated affects functions protein substrates number ways, including cellular localization, stability protein/protein interaction. Particularly, has been shown to intricate crosstalk with phosphorylation as they both modify residues. Aberrant on various implicated many diseases, neurodegenerative diabetes cancers. However, role immune cell lineages less explored. This review summarizes current understanding fundamental biochemistry O-GlcNAcylation, discusses molecular mechanisms regulates maturation cells. In brief, promotes proliferation, activation T B inflammatory antiviral responses macrophages. function activated neutrophils, but inhibits activity nature killer

Language: Английский

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