Inhibition of Phorbol Ester-induced Mouse Skin Tumor Promotion and COX-2 Expression by Celecoxib: C/EBP as a Potential Molecular Target.
- Author:
Kyung Soo CHUN
1
;
Joydeb Kumar KUNDU
;
Kwang Kyun PARK
;
Won Yoon CHUNG
;
Young Joon SURH
Author Information
1. National Research Laboratory of Molecular Carcinogenesis and Chemoprevention, College of Pharmacy, Seoul National University, Korea. surh@plaza.snu.ac.kr
- Publication Type:Original Article
- Keywords:
Celecoxib;
Chemoprevention;
Mouse skin carcinogenesis;
Cyclooxygenase-2;
VEGF;
NF-kappaB;
C/EBP
- MeSH:
Animals;
Blotting, Western;
Carcinogenesis;
Carrier Proteins;
Chemoprevention;
Cyclooxygenase 2;
DNA;
Inflammation;
Mice*;
NF-kappa B;
Papilloma;
Protein Isoforms;
Skin*;
Transcription Factors;
Vascular Endothelial Growth Factor A;
Celecoxib
- From:Cancer Research and Treatment
2006;38(3):152-158
- CountryRepublic of Korea
- Language:English
-
Abstract:
PURPOSE: Inflammation acts as a driving force for the development of cancer. Multiple lines of evidence suggest that nonsteroidal anti-inflammatory drugs, especially those that specifically target cyclooxygenase-2 (COX-2), are effective in preventing certain cancers. The present study was aimed at investigating the antitumor promoting potential of celecoxib in chemically induced mouse skin tumorigenesis, as well as elucidating the underlying molecular mechanisms. MATERIALS AND METHODS: To study the antitumor promoting effects of celecoxib, we used the classical two-stage mouse skin tumorigenesis model that involves initiation with a single application of 7,12-dimethylbenz[alpha]anthracene (DMBA) followed by promotion with repeated applications of 12-O-tetradecanoylphorbol-13-acetate (TPA). The effects of celecoxib on the expression of COX-2, vascular endothelial growth factor (VEGF), p65 and the different isoforms of CCAAT/enhancer binding protein (C/EBP) were examined by performing Western blot analysis. Electrophoretic mobility gel shift assay was used to examine the effects of celecoxib on the TPA-induced DNA binding activities of various transcription factors. RESULTS: Our study revealed that topical application of celecoxib (10 micromol) significantly reduced the multiplicity of papillomas in DMBA-initiated and TPA-promoted mouse skin. Pretreatment with celecoxib also diminished the expression of COX-2 and VEGF in the mouse skin papillomas. Pretreatment with celecoxib attenuated DNA binding of transcription factor (C/EBP) in the TPA-stimulated mouse skin. Moreover, celecoxib suppressed the TPA-induced nuclear expression of C/EBPdelta, but not C/EBPbeta, in mouse skin in vivo. CONCLUSION: Our study demonstrates the inhibitory effects of celecoxib on mouse skin tumor promotion, which was associated with a decreased expression of COX-2 and VEGF, as well as inhibition of C/EBP activation.
