%0 Journal Article %A Jong-Eun Kim %A Joe Eun Son %A Young Jin Jang %A Dong Eun Lee %A Nam Joo Kang %A Sung Keun Jung %A Yong-Seok Heo %A Ki Won Lee %A Hyong Joo Lee %T Luteolin, a Novel Natural Inhibitor of Tumor Progression Locus 2 Serine/Threonine Kinase, Inhibits Tumor Necrosis Factor-α-Induced Cyclooxygenase-2 Expression in JB6 Mouse Epidermis Cells %D 2011 %R 10.1124/jpet.111.179200 %J Journal of Pharmacology and Experimental Therapeutics %P 1013-1022 %V 338 %N 3 %X 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. %U https://jpet.aspetjournals.org/content/jpet/338/3/1013.full.pdf