IL-6/JAK2-dependent G6PD phosphorylation promotes nucleotide synthesis and supports tumor growth.
G6PD
JAK2
Nucleotide metabolism
Pentose phosphate pathway
Tumorigenesis
Journal
Molecular metabolism
ISSN: 2212-8778
Titre abrégé: Mol Metab
Pays: Germany
ID NLM: 101605730
Informations de publication
Date de publication:
Dec 2023
Dec 2023
Historique:
received:
12
08
2023
revised:
16
10
2023
accepted:
06
11
2023
medline:
28
11
2023
pubmed:
11
11
2023
entrez:
10
11
2023
Statut:
ppublish
Résumé
Tumor cells hijack inflammatory mechanisms to promote their own growth. IL-6 is one of the major cytokines, and is frequently upregulated in tumors. The pentose phosphate pathway (PPP) generates the indispensable building blocks to produce various nucleotides. Here we aimed to determine whether and how PPP is timely tuned in response to IL-6 to support tumor growth. Protein expression was examined by immunoblot. Protein interaction was examined by immunoprecipitation. Tumor cell proliferation in in vitro culture was examined by BrdU assay and colony formation assay. Tumor cell proliferation in mouse xenograft model was examined by Ki-67 staining. Here we show that the metabolic flux of PPP and enzymatic activity of glucose-6-phosphate dehydrogenase (G6PD) is rapidly induced under IL-6 treatment, without obvious changes in G6PD expression level. Mechanistically, Janus kinase 2 (JAK2) phosphorylates G6PD Y437 under IL-6 treatment, which accentuates G6PD enzymatic activity by promoting G6PD binding with its substrate G6P. Further, JAK2-dependent G6PD Y437 phosphorylation is required for IL-6-induced nucleotide biosynthesis and tumor cell proliferation, and is associated with the progression of oral squamous cell carcinoma. Our findings report a new mechanism implicated in the crosstalk between tumor cells and inflammatory microenvironment, by which JAK2-dependent activation of G6PD governs nucleotide synthesis to support tumor cell proliferation, thereby highlighting its value as a potential anti-tumor target.
Identifiants
pubmed: 37949355
pii: S2212-8778(23)00170-9
doi: 10.1016/j.molmet.2023.101836
pmc: PMC10692918
pii:
doi:
Substances chimiques
Oxidoreductases
EC 1.-
Interleukin-6
0
Janus Kinase 2
EC 2.7.10.2
Glucose 1-Dehydrogenase
EC 1.1.1.47
Phosphates
0
Nucleotides
0
JAK2 protein, human
EC 2.7.10.2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
101836Informations de copyright
Copyright © 2023 The Author(s). Published by Elsevier GmbH.. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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