Exp Mol Med.  2011 Dec;43(12):669-675. 10.3858/emm.2011.43.12.077.

Rottlerin enhances IL-1beta-induced COX-2 expression through sustained p38 MAPK activation in MDA-MB-231 human breast cancer cells

• Park EJ
• Kwon TK

• KMID: 1058704
• DOI: http://doi.org/10.3858/emm.2011.43.12.077

Abstract

Cyclooxygenase-2 (COX-2) is an important enzyme in inflammation. In this study, we investigated the underlying molecular mechanism of the synergistic effect of rottlerin on interleukin1beta (IL-1beta)-induced COX-2 expression in MDA-MB-231 human breast cancer cell line. Treatment with rottlerin enhanced IL-1beta-induced COX-2 expression at both the protein and mRNA levels. Combined treatment with rottlerin and IL-1beta significantly induced COX-2 expression, at least in part, through the enhancement of COX-2 mRNA stability. In addition, rottlerin and IL-1beta treatment drove sustained activation of p38 Mitogen-activated protein kinase (MAPK), which is involved in induced COX-2 expression. Also, a pharmacological inhibitor of p38 MAPK (SB 203580) and transient transfection with inactive p38 MAPK inhibited rottlerin and IL-1beta-induced COX-2 upregulation. However, suppression of protein kinase C delta (PKC delta) expression by siRNA or overexpression of dominant-negative PKC delta (DN-PKC-delta) did not abrogate the rottlerin plus IL-1beta-induced COX-2 expression. Furthermore, rottlerin also enhanced tumor necrosis factor-alpha (TNF-alpha), phorbol myristate acetate (PMA), and lipopolysaccharide (LPS)-induced COX-2 expression. Taken together, our results suggest that rottlerin causes IL-1beta-induced COX-2 upregulation through sustained p38 MAPK activation in MDA-MB-231 human breast cancer cells.

Keyword

breast neoplasms; cyclooxygenase-2; interleukin-1beta; p38 mitogen-activated protein kinases; RNA stability; rottlerin

MeSH Terms

Acetophenones/*pharmacology
Benzopyrans/*pharmacology
Breast Neoplasms/drug therapy/*genetics/immunology
Cell Line, Tumor
Cyclooxygenase 2/*genetics
Enzyme Activation/drug effects
Enzyme Inhibitors/*pharmacology
Female
Gene Expression Regulation, Neoplastic/*drug effects
Humans
Interleukin-1beta/*immunology
MAP Kinase Signaling System/drug effects
Mallotus Plant/chemistry
NF-kappa B/immunology
Protein Kinase C-delta/antagonists & inhibitors
Reactive Oxygen Species/immunology
p38 Mitogen-Activated Protein Kinases/*immunology