Nrf2-Keap1 and NF-kB-IkB Kinase Axes as Potential Chemopreventive Targets of Guggulsterone in Human Mammary Epithelial Cells : 인체유방상피세포에서 Nrf2-Keap1 및 NF-kB-IkB Kinase를 표적으로 하는 Guggulsterone의 화학 암예방 기전
- Inas Saleh Almazari
- Surh, Young-Joon
- Issue Date
- 서울대학교 대학원
- Guggulsterone (GS) is a phytosterol found in the gum resin of Commiphora mukul. GS has naturally two stereoisomers, E-guggulsterone (cis-GS) and Z-guggulsterone (trans-GS). The anti-inflammatory and antioxidant effects of both GS stereoisomers were explored in human mammary epithelial (MCF10A) cells. cis-GS upregulated the expression of the antioxidant enzyme heme oxygenase-1 (HO-1) to a greater extent than trans-GS in MCF10A cells. cis-GS induced HO-1 expression in dose- and time-dependent manners. NF-E2-related factor (Nrf2) is a basic-leucine zipper transcription factor that plays a key role in regulating the antioxidant/electrophile response element (ARE/EpRE)-mediated expression of various phase-II detoxifying or antioxidant enzymes including HO-1. cis-GS (20 microM) induced the nuclear translocation and ARE/DNA binding activity of Nrf2 in MCF10A cells. In addition, GS pretreatment and co-treatment suppressed 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced expression of cyclooxygenase-2 (COX-2) in MCF10A cells. Again, cis-GS was more potent than the trans-isomer, which might be due to its greater Nrf2-induced antioxidative activity. TPA-induced NF-kB/DNA binding activity was markedly suppressed by cis-GS co-treatment for 2 h in MCF10A cells in a concentration-dependent manner. In an attempt to investigate the role of Nrf2 activation in the anti-inflammatory effect of GS, expression of both HO-1 and COX-2 induced by cis-GS treatment was examined in cells transfected with Nrf2-siRNA. COX-2 levels were noticeably elevated in Nrf2-knocked down cells upon TPA treatment compared to cells transfected with scrambled siRNA. cis-GS co-treatment inhibited TPA-induced phosphorylation of IκBα and p65 in a concentration dependent manner. Moreover, co-treatment of MCF10A cells with cis-GS (25 µM) for 2 h inhibited the TPA-induced phosphorylation of IKKalpha/beta. These findings suggest that cis-GS by providing the cells with the acquired antioxidant and anti-inflammatory defense capacity, confers protection against carcinogenesis.
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