S-Space Graduate School of Convergence Science and Technology (융합과학기술대학원) Dept. of Molecular and Biopharmaceutical Sciences (분자의학 및 바이오제약학과) Journal Papers (저널논문_분자의학 및 바이오제약학과)
Sulforaphane inhibits phorbol ester-stimulated IKK-NF-kappa B signaling and COX-2 expression in human mammary epithelial cells by targeting NF-kappa B activating kinase and ERK
- Kim, Ha-Na; Kim, Do-Hee; Kim, Eun-Hee; Lee, Mee-Hyun; Kundu, Joydeb Kumar; Na, Hye-Kyung; Cha, Young-Nam; Surh, Young-Joon
- Issue Date
- Cancer Letters, Vol.351 No.1, pp.41-49
- Sulforaphane; Cyclooxygenase-2; NF-kappa B-activating kinase; IkappaB kinase; Chemoprevention
- Sulforaphane, an isothiocyanate present in cruciferous vegetables, has been reported to possess anti-inflammatory and cancer chemopreventive properties. However, the molecular mechanisms by which sulforaphane suppresses inflammation and carcinogenesis are yet to be fully elucidated. Since the aberrant expression of cyclooxygenase-2 (COX-2) links inflammation and cancer, the present study was aimed to elucidate the mechanisms by which sulforaphane modulates COX-2 overexpression in human mammary epithelial (MCF-10A) cells stimulated with a prototypic tumor promoter 12-O-tetradecanoylphorbol-beta-acetate (TPA). Treatment of MCF-10A cells with sulforaphane significantly inhibited TPA-induced expression of COX-2 protein and its mRNA transcript. Transient transfection of cells with deletion mutant constructs of COX-2 promoter revealed that the transcription factor nuclear factor-kappaB (NF-kappa B) plays a key role in TPA-induced COX-2 expression in MCF-10A cells. Pretreatment with sulforaphane significantly attenuated nuclear localization, DNA binding and the transcriptional activity of NF-kappa B through inhibition of phosphorylation and subsequent degradation of I kappa B alpha in MCF-10A cells stimulated with TPA. Sulforaphane also attenuated TPA-induced activation of I kappa B kinases (IKK), NF-kappa B-activating kinase (NAK) and extracellular signal-regulated kinase-1/2 (ERK1/2). Pharmacological inhibition of IKK or transient transfection of cells with dominant-negative mutant forms of this kinase abrogated TPA-induced NF-kappa B activation and COX-2 expression. In addition, the blockade of ERK1/2 activation negated the catalytic activity of IKK alpha, but not that of IKK beta, whereas silencing NAK by specific siRNA abrogated the IKK beta activity in TPA-treated cells. Taken together, sulforaphane inhibits TPA-induced NF-kappa B activation and COX-2 expression in MCF-10A cells by blocking two distinct signaling pathways mediated by ERK1/2-IKK alpha and NAK-IKK beta. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
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