The hexosamine biosynthetic pathway and cancer: Current knowledge and future therapeutic strategies

C, Lam; Low, Jin-Yih; Tran, Phuoc T.; Wang, Hailun

doi:10.1016/j.canlet.2021.01.010

Cited by 59 publications

(51 citation statements)

References 84 publications

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“…Then, GlcNAc-6-P is catalytically translocated to GlcNAc-1-P by AGM [ 139 ]. It is worth noting that the only difference of HBP in prokaryotes is that GlcN-6-P is isomerized to GlcN-1-P and then GlcN-1-P is acetylated to form GlcNAc-1-P [ 140 ]. The HBP process in eukaryotes is as shown above.…”

Section: Dynamic O -Glcnacylation Cycle and Hexosa...mentioning

confidence: 99%

O-GlcNAcylation: The Underestimated Emerging Regulators of Skeletal Muscle Physiology

Liu

Fan

et al. 2022

Cells

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O-GlcNAcylation is a highly dynamic, reversible and atypical glycosylation that regulates the activity, biological function, stability, sublocation and interaction of target proteins. O-GlcNAcylation receives and coordinates different signal inputs as an intracellular integrator similar to the nutrient sensor and stress receptor, which target multiple substrates with spatio-temporal analysis specifically to maintain cellular homeostasis and normal physiological functions. Our review gives a brief description of O-GlcNAcylation and its only two processing enzymes and HBP flux, which will help to better understand its physiological characteristics of sensing nutrition and environmental cues. This nutritional and stress-sensitive properties of O-GlcNAcylation allow it to participate in the precise regulation of skeletal muscle metabolism. This review discusses the mechanism of O-GlcNAcylation to alleviate metabolic disorders and the controversy about the insulin resistance of skeletal muscle. The level of global O-GlcNAcylation is precisely controlled and maintained in the “optimal zone”, and its abnormal changes is a potential factor in the pathogenesis of cancer, neurodegeneration, diabetes and diabetic complications. Although the essential role of O-GlcNAcylation in skeletal muscle physiology has been widely studied and recognized, it still is underestimated and overlooked. This review highlights the latest progress and potential mechanisms of O-GlcNAcylation in the regulation of skeletal muscle contraction and structural properties.

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Section: Dynamic O -Glcnacylation Cycle and Hexosa...mentioning

confidence: 99%

O-GlcNAcylation: The Underestimated Emerging Regulators of Skeletal Muscle Physiology

Liu

Fan

et al. 2022

Cells

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“…In fact, the inhibition of glutamine-fructose-6-phosphate transaminase 2 (GFPT2) more potently suppresses tumor growth in cell culture, xenografts and genetically engineered mouse models of NSCLC mutated in KRAS/LKB1 ( 114 ). The hexosamine biosynthesis pathway is a branch of glycolysis and there is increasing evidence that inhibition of this pathway may suppress tumor cell growth, enhance tumor response to conventional therapy, stimulate immune response and reduce cancer resistance, thus emerging as a possible therapeutic target ( 115 ).…”

Section: Targeting Lkb1 In Metabolismmentioning

confidence: 99%

LKB1: Can We Target an Hidden Target? Focus on NSCLC

et al. 2022

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LKB1 (liver kinase B1) is a master regulator of several processes such as metabolism, proliferation, cell polarity and immunity. About one third of non-small cell lung cancers (NSCLCs) present LKB1 alterations, which almost invariably lead to protein loss, resulting in the absence of a potential druggable target. In addition, LKB1-null tumors are very aggressive and resistant to chemotherapy, targeted therapies and immune checkpoint inhibitors (ICIs). In this review, we report and comment strategies that exploit peculiar co-vulnerabilities to effectively treat this subgroup of NSCLCs. LKB1 loss leads to an enhanced metabolic avidity, and treatments inducing metabolic stress were successful in inhibiting tumor growth in several preclinical models. Biguanides, by compromising mitochondria and reducing systemic glucose availability, and the glutaminase inhibitor telaglenastat (CB-839), inhibiting glutamate production and reducing carbon intermediates essential for TCA cycle progression, have provided the most interesting results and entered different clinical trials enrolling also LKB1-null NSCLC patients. Nutrient deprivation has been investigated as an alternative therapeutic intervention, giving rise to interesting results exploitable to design specific dietetic regimens able to counteract cancer progression. Other strategies aimed at targeting LKB1-null NSCLCs exploit its pivotal role in modulating cell proliferation and cell invasion. Several inhibitors of LKB1 downstream proteins, such as mTOR, MEK, ERK and SRK/FAK, resulted specifically active on LKB1-mutated preclinical models and, being molecules already in clinical experimentation, could be soon proposed as a specific therapy for these patients. In particular, the rational use in combination of these inhibitors represents a very promising strategy to prevent the activation of collateral pathways and possibly avoid the potential emergence of resistance to these drugs. LKB1-null phenotype has been correlated to ICIs resistance but several studies have already proposed the mechanisms involved and potential interventions. Interestingly, emerging data highlighted that LKB1 alterations represent positive determinants to the new KRAS specific inhibitors response in KRAS co-mutated NSCLCs. In conclusion, the absence of the target did not block the development of treatments able to hit LKB1-mutated NSCLCs acting on several fronts. This will give patients a concrete chance to finally benefit from an effective therapy.

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“…Two enzymes regulate O -GlcNAcylation: O -GlcNAc transferase (OGT) and O- GlcNAc hexosaminidase (OGA), whose donor substrate is UDP- N -acetylglucosamine (UDP-GlcNAc) ( Olivier-Van Stichelen et al, 2012 ). O- GlcNAcylation can be considered a transverse regulatory mechanism, “rheostat”, that could control the intensity of the signal through different pathways according to the nutritional status of the cell: being the activity of OGT dependent on the concentration of UDP-GlcNAc ( Issad et al, 2010 ), which is produced by the hexosamine biosynthetic pathway (HBP), this substrate is also used in the synthesis of N- and O -glycans mucin-type, ( Figure 3 ) ( Lam et al, 2021 ). Recently, Olson et al found that glucose metabolism via the HBP was only ∼0.006% of the glycolytic efflux in ex vivo mouse heart ( Olson et al, 2020 ), this is a value lower than the cited estimate of 2–3% of glucose uptake consumed by the HBP, calculated from cultured adipocytes ( Marshall et al, 1991 ).…”

Section: Glycosylationmentioning

confidence: 99%

An Overview of Glycosylation and its Impact on Cardiovascular Health and Disease

Loaeza-Reyes

Zenteno

Moreno-Rodríguez

et al. 2021

Front. Mol. Biosci.

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The cardiovascular system is a complex and well-organized system in which glycosylation plays a vital role. The heart and vascular wall cells are constituted by an array of specific receptors; most of them are N- glycosylated and mucin-type O-glycosylated. There are also intracellular signaling pathways regulated by different post-translational modifications, including O-GlcNAcylation, which promote adequate responses to extracellular stimuli and signaling transduction. Herein, we provide an overview of N-glycosylation and O-glycosylation, including O-GlcNAcylation, and their role at different levels such as reception of signal, signal transduction, and exogenous molecules or agonists, which stimulate the heart and vascular wall cells with effects in different conditions, like the physiological status, ischemia/reperfusion, exercise, or during low-grade inflammation in diabetes and aging. Furthermore, mutations of glycosyltransferases and receptors are associated with development of cardiovascular diseases. The knowledge on glycosylation and its effects could be considered biochemical markers and might be useful as a therapeutic tool to control cardiovascular diseases.

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The hexosamine biosynthetic pathway and cancer: Current knowledge and future therapeutic strategies

Cited by 59 publications

References 84 publications

O-GlcNAcylation: The Underestimated Emerging Regulators of Skeletal Muscle Physiology

O-GlcNAcylation: The Underestimated Emerging Regulators of Skeletal Muscle Physiology

LKB1: Can We Target an Hidden Target? Focus on NSCLC

An Overview of Glycosylation and its Impact on Cardiovascular Health and Disease

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