An unusual nicotinamide derivative, 4-pyridone-3-carboxamide ribonucleoside (4PYR), is a novel endothelial toxin and oncometabolite.
Animals
Carcinogens
/ pharmacology
Cell Line, Tumor
Cell Membrane Permeability
Cell Transformation, Neoplastic
/ chemically induced
Disease Models, Animal
Endothelial Cells
/ drug effects
Extracellular Space
/ metabolism
Female
Humans
Hydrolysis
Intracellular Space
/ metabolism
Mice
Niacinamide
/ analogs & derivatives
Receptors, Estrogen
/ antagonists & inhibitors
Journal
Experimental & molecular medicine
ISSN: 2092-6413
Titre abrégé: Exp Mol Med
Pays: United States
ID NLM: 9607880
Informations de publication
Date de publication:
09 2021
09 2021
Historique:
received:
29
07
2020
accepted:
17
03
2021
revised:
10
03
2021
pubmed:
29
9
2021
medline:
30
3
2022
entrez:
28
9
2021
Statut:
ppublish
Résumé
Our recent studies identified a novel pathway of nicotinamide metabolism that involves 4-pyridone-3-carboxamide-1-β-D-ribonucleoside (4PYR) and demonstrated its endothelial cytotoxic effect. This study tested the effects of 4PYR and its metabolites in experimental models of breast cancer. Mice were divided into groups: 4T1 (injected with mammary 4T1 cancer cells), 4T1 + 4PYR (4PYR-treated 4T1 mice), and control, maintained for 2 or 21 days. Lung metastasis and endothelial function were analyzed together with blood nucleotides (including 4PYR), plasma amino acids, nicotinamide metabolites, and vascular ectoenzymes of nucleotide catabolism. 4PYR metabolism was also evaluated in cultured 4T1, MDA-MB-231, MCF-7, and T47D cells. An increase in blood 4PYR in 4T1 mice was observed at 2 days. 4PYR and its metabolites were noticed after 21 days in 4T1 only. Higher blood 4PYR was linked with more lung metastases in 4T1 + 4PYR vs. 4T1. Decreased L-arginine, higher asymmetric dimethyl-L-arginine, and higher vascular ecto-adenosine deaminase were observed in 4T1 + 4PYR vs. 4T1 and control. Vascular relaxation caused by flow-dependent endothelial activation in 4PYR-treated mice was significantly lower than in control. The permeability of 4PYR-treated endothelial cells was increased. Decreased nicotinamide but enhanced nicotinamide metabolites were noticed in 4T1 vs. control. Reduced N-methylnicotinamide and a further increase in Met2PY were observed in 4T1 + 4PYR vs. 4T1 and control. In cultured breast cancer cells, estrogen and progesterone receptor antagonists inhibited the production of 4PYR metabolites. 4PYR formation is accelerated in cancer and induces metabolic disturbances that may affect cancer progression and, especially, metastasis, probably through impaired endothelial homeostasis. 4PYR may be considered a new oncometabolite.
Identifiants
pubmed: 34580423
doi: 10.1038/s12276-021-00669-w
pii: 10.1038/s12276-021-00669-w
pmc: PMC8492732
doi:
Substances chimiques
Carcinogens
0
Receptors, Estrogen
0
Niacinamide
25X51I8RD4
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1402-1412Informations de copyright
© 2021. The Author(s).
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