https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4983259/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4983259/bin/nihms-797946-f0001.jpg
The Hexosamine Biosynthetic Pathway (HBP) is highly dependent on multiple metabolic nutrients including glucose, glutamine and acetyl-CoA.
Increased flux through HBP
leads to elevated post-translational addition of β-D-N-acetylglucosamine
sugars to nuclear and cytoplasmic proteins.
Increased total
O-GlcNAcylation is emerging as a general characteristic of cancer cells
and recent studies suggest that O-GlcNAcylation is a central
communicator of nutritional status to control key signaling and
metabolic pathways that regulate multiple cancer cell phenotypes.
This
review summarizes our current understanding of changes of O-GlcNAc
cycling enzymes in cancer, the role of O-GlcNAcylation in tumorigenesis
and the current challenges in targeting this pathway therapeutically.
Keywords: glycosylation,
signaling, hexosamine biosynthetic pathway, O-GlcNAcylation, OGT,
cancer, metabolism, invasion, metastasis, angiogenesis, epithelial, ER
stress, HIF-1α
The Hexosamine Pathway Intersects with the Receptor Tyrosine Kinase/AMPK/mTOR Pathway
In
left panel, the hexosamine pathway controls O-GlcNAcylation of nuclear
and cytoplasmic proteins. A small fraction (2-5%) of glucose enters the
HBP and fructose-6-phosphate is converted to glucosamine-6-phosphate by
the rate-limiting enzyme of this pathway glutamine:fructose-6-
amidotransferase (GFAT). UDP-N-acetylglucosamine (UDP-GlcNAc) is
generated in subsequent steps and used as substrate by O-GlcNAc
transferase (OGT) to add GlcNAc to serine or threonine residues of
nuclear or cytoplasmic target proteins. O-GlcNAc modifications can be
removed from proteins by the glycoside hydrolase O-GlcNAcase (OGA). In
right panel, the receptor tyrosine kinase (RTK)-mediated signaling
pathways converge on mTOR to regulate key transcription factors involved
in cancer metabolism including HIF-1α, c-MYC, and SREBP-1. LKB1/AMPK
negatively regulate mTOR pathway and metabolism. OGT and O-GlcNAcylation
can intersect with this pathway at level of AMPK and regulation of key
metabolic transcription factors HIF-1α and c-Myc. Abbreviations: HK2,
hexokinase, PFKFB3,
6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase, isoform 3; PDK1,
pyruvate dehydrogenase kinase, isozyme 1; PGK, phosphoglycerate kinase;
PKM2, pyruvate kinase M2 isoform; LDHA, lactate dehydrogenase A; GLS1,
glutaminae 1; ACLY, ATP citrate lyase; FASN, fatty acid synthase; ACC1,
acetyl-CoA carboxylase 1.-
..
we implicate O-GlcNAcylation as a central component linking metabolism to invasion and metastasis via a AMPK/SIRT1/FOXM1 axis..
Implications and Future Directions
Research
into the evolving role of O-GlcNAcylation in normal biology and
pathologies will continue to expand our understanding of the role of
this modification in disease states such as cancer. Although there is
ample evidence for a role of OGT in many “Hallmarks of Cancer” (Figure 2),
it is still little evidence that OGT or O-GlcNAcylation may play a role
in enabling replicative immortality or avoiding immune destruction. We
must continue to expand our insight into the roles of OGT and
O-GlcNAcylation in cancer and adult biology. We currently do not
understand the role OGT plays in many adult systems. OGT knockout is
embryonic lethal, owing to its role in development and therefore must
play a strong role in developing cells 60.
We can hypothesize that OGT and O-GlcNAc may play some role in adult
stem cells and perhaps cancer stem cells, however these avenues of
investigation have not yet been explored. New tools for genetic
manipulation, such as the CRISPR-Cas9 system or novel mouse models, will
accelerate our comprehension of the complex function of OGT in both
normal biology and cancer. In addition, the discovery and improvement of
new and existing OGT inhibitors will also help in understanding the
role of OGT in normal biology and cancer. These new and more specific
OGT inhibitors may also provide novel and effective therapeutic agents
for cancers that exhibit deregulated O-GlcNAcylation.
Päivitys: hexosaminitie ja COVID-19?
Working Hypothesis for Glucose Metabolism and SARS-CoV-2 Replication: Interplay Between the Hexosamine Pathway and Interferon RF5 Triggering Hyperinflammation. Role of BCG Vaccine?
Front Endocrinol (Lausanne). 2020 Jul 7;11:514. doi: 10.3389/fendo.2020.00514. eCollection 2020.
PMID: 32733388
Free PMC article.
No abstract available.
Tämä kuva sytokiinimyrskyn provosoitumsiessa Covid-19 taudissa kuvana on lisätty 26.9.2022. Katson tästä erikseen 26.9.2022 IRF5 osuus.
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