Abstract |
Cardiac glycosides, which are inhibitors of Na(+)/K(+)- ATPase, are classified into cardenolides and bufadienolides. We have recently shown that two cardenolide glycosides, ouabain and odoroside A, inhibit Na(+)/K(+)- ATPase, thereby preventing nuclear factor κB-inducible protein expression by blocking Na(+)-dependent amino acid transport. In this study, we investigated the mechanism of action of cardenolide aglycones in tumor necrosis factor α (TNF-α)-induced gene expression. Ouabagenin, digitoxigenin, and digoxigenin were found to inhibit the TNF-α-induced cell-surface expression of intercellular adhesion molecule-1 (ICAM-1) in human lung carcinoma A549 cells. Those cardenolide aglycones did not inhibit the TNF-α-induced expression of ICAM-1 mRNA, but strongly inhibited the TNF-α-induced expression of ICAM-1 as translation product. The inhibition of the TNF-α-induced ICAM-1 expression by ouabagenin, digitoxigenin, and digoxigenin was significantly reversed by the ectopic expression of ouabain-resistant rat Na(+)/K(+)- ATPase α1 isoform. Moreover, knockdown of Na(+)/K(+)- ATPase α1 isoform augmented the inhibition of the TNF-α-induced ICAM-1 expression by ouabagenin or ouabain. These results clearly indicate that cardenolide aglycones inhibit the TNF-α-induced ICAM-1 expression at the translation step by blocking Na(+)/K(+)- ATPase.
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Authors | Yuji Okina, Fumihiko Takeuchi, Tomonobu Yokomichi, Yohei Takada, Takao Kataoka |
Journal | Biological & pharmaceutical bulletin
(Biol Pharm Bull)
Vol. 38
Issue 1
Pg. 39-47
( 2015)
ISSN: 1347-5215 [Electronic] Japan |
PMID | 25744456
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- ICAM1 protein, human
- RNA, Messenger
- RNA, Small Interfering
- Tumor Necrosis Factor-alpha
- Intercellular Adhesion Molecule-1
- Digitoxigenin
- Ouabain
- Sodium-Potassium-Exchanging ATPase
- Digoxigenin
- ouabagenin
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Topics |
- Animals
- Cell Line
- Cell Line, Tumor
- Cell Survival
(drug effects)
- Digitoxigenin
(pharmacology)
- Digoxigenin
(pharmacology)
- Humans
- Intercellular Adhesion Molecule-1
(genetics, metabolism)
- Ouabain
(analogs & derivatives, pharmacology)
- Protein Biosynthesis
(drug effects)
- RNA, Messenger
(metabolism)
- RNA, Small Interfering
(genetics)
- Rats
- Sodium-Potassium-Exchanging ATPase
(antagonists & inhibitors, genetics, metabolism)
- Tumor Necrosis Factor-alpha
(metabolism)
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