Kim Do-Hee, Kim Eun-Hee, Na Hye-Kyung, Surh Young-Joon
National Research Laboratory of Molecular Carcinogenesis and Chemoprevention, College of Pharmacy, Seoul National University, Seoul, Korea.
Ann N Y Acad Sci. 2009 Aug;1171:202-9. doi: 10.1111/j.1749-6632.2009.04913.x.
Cyclopentenone prostaglandins (cyPGs) exert diverse cellular functions, such as anti-inflammatory and cytoprotective effects, via multiple mechanisms. CyPGs, especially those of the A and J series, are characterized by the presence of a chemically reactive alpha,beta-unsaturated carbonyl group. 15-Deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), a representative cyPG of the J series, has been reported to directly inhibit the activity of redox-sensitive transcription factors, such as activator protein-1 and nuclear factor-kappaB. In the present study, we examined the effects of 15d-PGJ(2) on activation of p53 tumor suppressor in human breast cancer (MCF-7) cells. MCF-7 cells treated with 15d-PGJ(2) exhibited elevated p53 protein expression in time- and concentration-related manners, whereas prostaglandin A(2) (PGA(2)) and the nonprostaglandin derivative 2-cyclopenten-1-one exerted an effect to a lesser extent than did 15d-PGJ(2). In addition, MCF-7 cells exposed to 15d-PGJ(2) significantly accumulated p53 in both cytosolic and nuclear fractions. Despite the elevated levels of p53, its DNA-binding activity was reduced in 15d-PGJ(2)-treated MCF-7 cells. Moreover, isolated MCF-7 nuclear extracts directly treated with 15d-PGJ(2) exhibite diminished DNA-binding ability of p53, while the same concentration of PGA(2) or 2-cyclopenten-1-one was much less inhibitory. Thus, the electrophilic carbon center located in the alpha,beta-unsaturated carbonyl moiety of the cyclopentenone ring might be critical for the control of DNA-binding activity as well as cellular levels of p53 by 15d-PGJ(2).
环戊烯酮前列腺素（cyPGs）通过多种机制发挥多种细胞功能，如抗炎和细胞保护作用。CyPGs，尤其是A系列和J系列的CyPGs，其特征在于存在化学反应性的α，β-不饱和羰基。15-脱氧-Δ（12,14）-前列腺素J2（15d-PGJ2）是J系列的代表性cyPG，据报道它可直接抑制氧化还原敏感转录因子的活性，如激活蛋白-1和核因子-κB。在本研究中，我们检测了15d-PGJ2对人乳腺癌（MCF-7）细胞中p53肿瘤抑制因子激活的影响。用15d-PGJ2处理的MCF-7细胞以时间和浓度相关的方式表现出p53蛋白表达升高，而前列腺素A2（PGA2）和非前列腺素衍生物2-环戊烯-1-酮的作用程度小于15d-PGJ2。此外，暴露于15d-PGJ2的MCF-7细胞在细胞质和细胞核部分均显著积累p53。尽管p53水平升高，但其在经15d-PGJ2处理的MCF-7细胞中的DNA结合活性降低。此外，直接用15d-PGJ2处理的分离的MCF-7细胞核提取物表现出p53的DNA结合能力减弱，而相同浓度的PGA2或2-环戊烯-1-酮的抑制作用要小得多。因此，位于环戊烯酮环α，β-不饱和羰基部分的亲电碳中心可能对于15d-PGJ2控制p53的DNA结合活性以及细胞水平至关重要。
