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Roles of ERK and p38 mitogen-activated protein kinases in phorbol ester-induced NF-kappaB activation and COX-2 expression in human breast epithelial cells.
Chem Biol Interact. 2008 Jan 30; 171(2):133-41.CB

Abstract

Inappropriate up-regulation of cyclooxygenase-2 (COX-2) has been implicated in pathogenesis of various types of human cancer. Thus, COX-2 has been recognized as an important target for the chemoprevention of several human malignancies including breast cancer. COX-2 expression is known to be regulated by the eukaryotic transcription factor NF-kappaB. In an attempt to link the NF-kappaB activation and COX-2 induction during mammary carcinogenesis, we have examined the effects of 12-O-tetradecanoylphorbol-13-acetate (TPA), a prototype tumor promoter and a mitogen, on NF-kappaB activation and COX-2 expression in the immortalized human breast epithelial cell line (MCF10A). Treatment of MCF10A cells with TPA resulted in transient induction of NF-kappaB DNA binding with maximal activation observed at 30 min. Increased DNA binding of NF-kappaB was accompanied by enhancement of its transcriptional activity as determined by the luciferase reporter gene assay. Under the same experimental conditions, expression of COX-2 mRNA and its protein product peaked at 2h and 4h, respectively. TPA treatment caused an increase in the production of prostaglandin E(2). Treatment of cells with the NF-kappaB inhibitor pyrrolidine dithiocarbamate resulted in significant suppression of TPA-induced COX-2 expression. TPA induced activation of ERK1/2 and p38 mitogen-activated protein kinases (MAPK) via phosphorylation. PD98059 (ERK inhibitor) and SB203580 (p38 MAPK inhibitor) down-regulated the COX-2 expression induced by TPA. Furthermore, TPA-induced COX-2 induction as well as NF-kappaB activation was blocked in MCF10A cells transfected with dominant negative mutant ERK1/2 or p38 MAPK. These results suggest that both p38 and ERK MAPKs activates NF-kappaB signaling, which in turn induces COX-2 expression in TPA-stimulated human mammary epithelial cells.

Authors+Show Affiliations

National Research Laboratory of Molecular Carcinogenesis and Chemoprevention, College of Pharmacy, Seoul National University, Seoul 151-742, South Korea.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17767925

Citation

Kim, Jung-Hwan, et al. "Roles of ERK and P38 Mitogen-activated Protein Kinases in Phorbol Ester-induced NF-kappaB Activation and COX-2 Expression in Human Breast Epithelial Cells." Chemico-biological Interactions, vol. 171, no. 2, 2008, pp. 133-41.
Kim JH, Na HK, Pak YK, et al. Roles of ERK and p38 mitogen-activated protein kinases in phorbol ester-induced NF-kappaB activation and COX-2 expression in human breast epithelial cells. Chem Biol Interact. 2008;171(2):133-41.
Kim, J. H., Na, H. K., Pak, Y. K., Lee, Y. S., Lee, S. J., Moon, A., & Surh, Y. J. (2008). Roles of ERK and p38 mitogen-activated protein kinases in phorbol ester-induced NF-kappaB activation and COX-2 expression in human breast epithelial cells. Chemico-biological Interactions, 171(2), 133-41.
Kim JH, et al. Roles of ERK and P38 Mitogen-activated Protein Kinases in Phorbol Ester-induced NF-kappaB Activation and COX-2 Expression in Human Breast Epithelial Cells. Chem Biol Interact. 2008 Jan 30;171(2):133-41. PubMed PMID: 17767925.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Roles of ERK and p38 mitogen-activated protein kinases in phorbol ester-induced NF-kappaB activation and COX-2 expression in human breast epithelial cells. AU - Kim,Jung-Hwan, AU - Na,Hye-Kyung, AU - Pak,Youngmi K, AU - Lee,Yun-Sil, AU - Lee,Su-Jae, AU - Moon,Aree, AU - Surh,Young-Joon, Y1 - 2007/07/26/ PY - 2007/02/16/received PY - 2007/06/28/revised PY - 2007/07/22/accepted PY - 2007/9/5/pubmed PY - 2008/5/6/medline PY - 2007/9/5/entrez SP - 133 EP - 41 JF - Chemico-biological interactions JO - Chem Biol Interact VL - 171 IS - 2 N2 - Inappropriate up-regulation of cyclooxygenase-2 (COX-2) has been implicated in pathogenesis of various types of human cancer. Thus, COX-2 has been recognized as an important target for the chemoprevention of several human malignancies including breast cancer. COX-2 expression is known to be regulated by the eukaryotic transcription factor NF-kappaB. In an attempt to link the NF-kappaB activation and COX-2 induction during mammary carcinogenesis, we have examined the effects of 12-O-tetradecanoylphorbol-13-acetate (TPA), a prototype tumor promoter and a mitogen, on NF-kappaB activation and COX-2 expression in the immortalized human breast epithelial cell line (MCF10A). Treatment of MCF10A cells with TPA resulted in transient induction of NF-kappaB DNA binding with maximal activation observed at 30 min. Increased DNA binding of NF-kappaB was accompanied by enhancement of its transcriptional activity as determined by the luciferase reporter gene assay. Under the same experimental conditions, expression of COX-2 mRNA and its protein product peaked at 2h and 4h, respectively. TPA treatment caused an increase in the production of prostaglandin E(2). Treatment of cells with the NF-kappaB inhibitor pyrrolidine dithiocarbamate resulted in significant suppression of TPA-induced COX-2 expression. TPA induced activation of ERK1/2 and p38 mitogen-activated protein kinases (MAPK) via phosphorylation. PD98059 (ERK inhibitor) and SB203580 (p38 MAPK inhibitor) down-regulated the COX-2 expression induced by TPA. Furthermore, TPA-induced COX-2 induction as well as NF-kappaB activation was blocked in MCF10A cells transfected with dominant negative mutant ERK1/2 or p38 MAPK. These results suggest that both p38 and ERK MAPKs activates NF-kappaB signaling, which in turn induces COX-2 expression in TPA-stimulated human mammary epithelial cells. SN - 0009-2797 UR - https://www.unboundmedicine.com/medline/citation/17767925/Roles_of_ERK_and_p38_mitogen_activated_protein_kinases_in_phorbol_ester_induced_NF_kappaB_activation_and_COX_2_expression_in_human_breast_epithelial_cells_ DB - PRIME DP - Unbound Medicine ER -