Abstract
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.
Highlights
Breast cancer is one of the main causes of mortality in females due to its high rate of metastasis into distant organs, such as the lungs and liver[1]
This study aimed to investigate the changes in 4PYR concentration and the effects of its derivatives on nucleotide and nicotinamide metabolism, as well as on metastasis in breast cancer using in vivo and in vitro models
On the 21st day of the experiment, we determined the blood concentrations of 4PYR derivatives and nucleotides associated with cell energetics (Fig. 1b−d), the lung metastasis number (Fig. 2), L-arginine metabolite concentrations (Fig. 3), vascular activities of extracellular nucleotide catabolism enzymes (Fig. 4) as indicators of endothelium condition, and NA metabolite concentrations (Fig. 6) in vivo
Summary
Breast cancer is one of the main causes of mortality in females due to its high rate of metastasis into distant organs, such as the lungs and liver[1]. There are currently no effective methods for metastasis treatment and prevention[2]. A better understanding of the mechanisms and the discovery of new markers would have a major impact on patient prognosis. Endothelial dysfunction is known to promote the development of various pathologies, including cancer. A dysfunctional vessel wall is a favorable environment for the intravasation of cancer cells—the process of tumor cell transmigration through the vessel wall into the circulation. The loss of endothelial integrity and permeability, observed in defective endothelia, facilitates cancer cell transendothelial migration[3]. One of the mechanisms underlying this deterioration is an active inflammatory process[4]
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