Odoroside A and ouabain inhibit Na+/K+-ATPase and prevent NF-kappaB-inducible protein expression by blocking Na+-dependent amino acid transport.

Abstract

Inflammatory cytokines, such as tumor necrosis factor (TNF)-alpha and interleukin-1 (IL-1), trigger the activation of transcription factor NF-kappaB that induces the expression of a variety of genes, including intercellular adhesion molecule (ICAM)-1. Odoroside A [3beta-O-(beta-D-diginosyl)-14-hydroxy-5beta,14beta-card-20(22)-enolide] was found to inhibit the cell-surface expression of ICAM-1 induced by TNF-alpha and IL-1 at comparable concentrations in human lung carcinoma A549 cells. In this study, the molecular mechanism underlying the inhibition of TNF-alpha-induced cell-surface ICAM-1 expression by odoroside A together with the specific Na(+)/K(+)-ATPase inhibitor ouabain was further investigated. Odoroside A and ouabain neither prevented IkappaBalpha degradation nor NF-kappaB translocation to the nucleus upon TNF-alpha stimulation. While odoroside A and ouabain had no inhibitory effect on the induction of ICAM-1 mRNA, they inhibited the TNF-alpha-induced ICAM-1 expression at the protein level. Consistent with these results, odoroside A and ouabain potently reduced de novo protein synthesis, largely due to its ability to block Na(+)-dependent transport of amino acids across the plasma membrane, but not to interfering with the translation machinery. As a direct molecular target, odoroside A was found to inhibit the ATP-hydrolyzing activity of Na(+)/K(+)-ATPase as potently as ouabain. These results clearly demonstrate that odoroside A and ouabain prevent NF-kappaB-inducible protein expression by blocking the Na(+)-dependent amino acid transport.

• Authors: Yohei Takada, Kentaro Matsuo, Hirotsugu Ogura, Liming Bai, Asami Toki, Liyan Wang, Masayoshi Ando, Takao Kataoka
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 78 Issue 9 Pg. 1157-66 (Nov 01 2009) ISSN: 1873-2968 [Electronic] England
• PMID: 19559678 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amino Acids
• Cardenolides
• DNA Primers
• Interleukin-1
• NF-kappa B
• Proteins
• RNA, Messenger
• Tumor Necrosis Factor-alpha
• odoroside
• Intercellular Adhesion Molecule-1
• Ouabain
• Sodium
• Sodium-Potassium-Exchanging ATPase

Topics

• Amino Acids (metabolism)
• Base Sequence
• Biological Transport (drug effects)
• Blotting, Western
• Cardenolides (pharmacology)
• Cell Line, Tumor
• DNA Primers
• Humans
• Intercellular Adhesion Molecule-1 (metabolism)
• Interleukin-1 (metabolism)
• NF-kappa B (antagonists & inhibitors, metabolism)
• Ouabain (pharmacology)
• Polymerase Chain Reaction
• Proteins (metabolism)
• RNA, Messenger (genetics)
• Sodium (metabolism)
• Sodium-Potassium-Exchanging ATPase (metabolism)
• Tumor Necrosis Factor-alpha (metabolism)