TY - JOUR T1 - 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 JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 1013 LP - 1022 DO - 10.1124/jpet.111.179200 VL - 338 IS - 3 AU - Jong-Eun Kim AU - Joe Eun Son AU - Young Jin Jang AU - Dong Eun Lee AU - Nam Joo Kang AU - Sung Keun Jung AU - Yong-Seok Heo AU - Ki Won Lee AU - Hyong Joo Lee Y1 - 2011/09/01 UR - http://jpet.aspetjournals.org/content/338/3/1013.abstract N2 - 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. ER -