Epigallocatechin gallate inhibits phorbol ester-induced activation of NF-kappa B and CREB in mouse skin: role of p38 MAPK.
The modulation of intracellular signaling network involved in an inappropriate expression of cyclooxygenase-2 (COX-2) is a pragmatic approach for chemoprevention with a wide variety of dietary phytochemicals. Epigallocatechin gallate (EGCG), a major green tea polyphenol, is one of the most extensively investigated chemopreventive agents. Our previous study revealed that EGCG inhibited expression of COX-2 and activation of mitogen-activated protein kinases (MAPKs) in mouse skin stimulated with a prototype tumor promotor 12-O-tetradecanoylphorbol-13-acetate (TPA). This study was aimed at identifying transcription factors as molecular targets of EGCG in downregulating COX-2 expression. We found that EGCG inhibited TPA-induced DNA binding of NF-kappaB and CREB in mouse skin in vivo. EGCG also suppressed TPA-induced phosphorylation and subsequent degradation of IkappaBalpha, and prevented nuclear translocation of p65. We also examined whether extracellular signal-regulated protein kinase (ERK) and p38 MAPK, which are known to regulate activation of NF-kappaB, can also modulate CREB DNA binding. Pretreatment with U0126 and SB203580, pharmacological inhibitors of ERK and p38 MAPK, respectively, showed that SB203580, but not U0126, attenuated TPA-induced CREB DNA binding in mouse skin. Taken together, EGCG inhibited TPA-induced DNA binding of NF-kappaB and CREB by blocking activation of p38 MAPK, which may provide a molecular basis of COX-2 inhibition by EGCG in mouse skin in vivo.
Kundu
Joydeb Kumar
JK
College of Pharmacy, Seoul National University, Shillim-dong, Kwanak-ku, Seoul 151-742, Korea.
Surh
Young-Joon
YJ
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D005260:Female; D051379:Mice; D008813:Mice, Inbred ICR; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012867:Skin / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*
D016588:Anticarcinogenic Agents; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D052246:Cyclooxygenase 2 Inhibitors; D016328:NF-kappa B; D002392:Catechin; C045651:epigallocatechin gallate; D048051:p38 Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate