Sulforaphane down-regulates COX-2 expression by activating p38 and inhibiting NF-kappaB-DNA-binding activity in human bladder T24 cells.
Cyclooxygenase-2 (COX-2) overexpression has been associated with the grade, prognosis and recurrence of transitional cell carcinoma (TCC) of the bladder. In this study, sulforaphane, a dietary isothiocyanate, down-regulated COX-2 expression in human bladder transitional cancer T24 cells at both transcriptional- and translational levels. Sulforaphane (5-20 microM) induced nuclear translocation of NF-kappaB and reduced its binding to the COX-2 promoter, a key mechanism for suppressing COX-2 expression by sulforaphane. Moreover, sulforaphane increased expression of p38 and phosphorylated-p38 protein. A specific inhibitor of p38 MAPK, SB202190, was used to further investigate its pivotal role in sulforaphane-mediated down-regulation of COX-2. Exposure of T24 cells to SB202190 1 hour prior to sulforaphane treatment abolished the effect of sulforaphane on COX-2 mRNA down-regulation, but enhanced COX-2 transcription. Furthermore, SB202190 alone induced NF-kappaB translocation to the nucleus, promoted NF-kappaB binding to the COX-2 promoter and resulted in up-regulation of COX-2 expression. Taken together, these data suggest that p38 is essential in sulforaphane-mediated COX-2 suppression and provide new insights into the molecular mechanisms of sulforaphane in the chemoprevention of bladder cancer.
Shan
Yujuan
Y
School of Medicine, Health Policy and Practice, University of East Anglia, Norwich NR4 7TJ, UK.
Wu
Kun
K
Wang
Wei
W
Wang
Shuran
S
Lin
Na
N
Zhao
Ruifang
R
Cassidy
Aedin
A
Bao
Yongping
Y
D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D017879:Isothiocyanates; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D013454:Sulfoxides; D013861:Thiocyanates / Q000494:pharmacology*; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D016588:Anticarcinogenic Agents; D007093:Imidazoles; D017879:Isothiocyanates; D016328:NF-kappa B; D011725:Pyridines; D013454:Sulfoxides; D013861:Thiocyanates; D051546:Cyclooxygenase 2; D048051:p38 Mitogen-Activated Protein Kinases; C016766:sulforaphane; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole