Abstract
Targeting tumor necrosis factor (TNF)-α-mediated signal pathways may be a promising strategy for developing chemopreventive agents, because TNF-α-mediated cyclooxygenase (COX)-2 expression plays a key role in inflammation and carcinogenesis. Luteolin [2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-4-chromenone] exerts anticarcinogenic effects, although little is known about the underlying molecular mechanisms and specific targets of this compound. In the present study, we found that luteolin inhibited TNF-α-induced COX-2 expression by down-regulating the transactivation of nuclear factor-κB and activator protein-1. Furthermore, luteolin inhibited TNF-α-induced phosphorylation of mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase 1/ERK/p90RSK, mitogen-activated protein kinase kinase 4/c-Jun N-terminal kinase/c-Jun, and Akt/p70S6K. However, it had no effect on the phosphorylation of p38. These effects of luteolin on TNF-α-mediated signaling pathways and COX-2 expression are similar to those achieved by blocking tumor progression locus 2 serine/threonine kinase (TPL2) using pharmacologic inhibitors and small interfering RNAs. Luteolin inhibited TPL2 activity in vitro and in TPL2 immunoprecipitation kinase assays by binding directly in an ATP-competitive manner. Overall, these results indicate that luteolin exerts potent chemopreventive activities, which primarily target TPL2.
Footnotes
This work was supported in part by the World Class University Program [Grant R31-2008-00-10056-0] and the National Leap Research Program [Grant 2010-0029233] through the National Research Foundation of Korea funded by the Ministry of Education, Science, and Technology, Republic of Korea.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.111.179200.
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ABBREVIATIONS:
- TNF
- tumor necrosis factor
- TNFR
- TNF-α receptor
- TPL2
- tumor progression locus 2 serine/threonine kinase
- siTPL2
- small interfering TLP2
- TPL2i
- TPL2 inhibitor, 4-(3-chloro-4-fluorophenylamino)-6-(pyridin-3-yl-methylamino)-3-cyano-[1,7]-naphthyridine
- COX
- cyclooxygenase
- AP-1
- activator protein-1
- NF-κB
- nuclear factor-κB
- ERK
- extracellular signal-regulated kinase
- FBS
- fetal bovine serum
- JNK
- c-Jun N-terminal kinase
- MAPK
- mitogen-activated protein kinase
- MEK1
- MAPK/ERK kinase 1
- MKK4
- mitogen-activated protein kinase kinase 4
- MEM
- minimum essential medium
- MTT
- 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
- G418
- (2R,3S,4R,5R,6S)-5-amino-6-[(1R,2S,3S,4R,6S)-4,6-diamino-3-[(2R,3R,4R,5R)-3,5-dihydroxy-5-methyl-4-methylaminooxan-2-yl]oxy-2-hydroxycyclohexyl]oxy-2-(1-hydroxyethyl)oxane-3,4-diol
- DTT
- dithiothreitol
- PMSF
- phenylmethylsulfonyl fluoride
- siRNA
- small interfering RNA
- siMock
- small interfering Mock.
- Received January 13, 2011.
- Accepted June 23, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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