Bui T, Straus D S
Biology Department, University of California, Riverside 92521-0121, USA.
Biochim Biophys Acta. 1998 Apr 1;1397(1):31-42. doi: 10.1016/s0167-4781(97)00214-5.
The molecular pathways by which the cyclopentenone prostaglandins (PGA and PGJ series) inhibit cell growth and tumorigenicity are poorly understood. These cellular responses may be caused by specific regulation of growth-related and stress-induced genes. A variety of prostaglandins were tested for their ability to regulate insulin-like growth factor-I (IGF-I) and Waf1 gene expression in C6 rat glioma cells. The prostaglandins (in order of potency) PGJ2 > PGA1 > PGA2, approximately PGD2 >> PGE2 all significantly repressed IGF-I gene expression. With the exception of PGE2, the same prostaglandins that repressed IGF-I also induced Waf1 gene expression. However, the order of potency for Waf1 induction was different than for IGF-I repression: PGA2 > PGA1 approximately PGJ2 > PGD2. The different order of potency of the prostaglandins in regulating IGF-I and Waf1 gene expression suggests that different intracellular signals may be involved in regulating the two genes. Augmentation of glutathione levels by pretreatment of cells with N-acetyl-L-cysteine attenuated the effect of PGA2 on IGF-I and Waf1 gene expression. conversely, depletion of the intracellular glutathione pool by pretreatment with buthionine sulfoximine potentiated the effect of PGA2 on the expression of both genes. These results suggest that conjugation with glutathione prevents the regulation of gene expression by PGA2. We also tested the effect of several simpler compounds that contain a five-membered ring system on IGF-I and Waf1 gene expression. 2-Cyclopenten-1-one, but not cyclopentene or cyclopentene, repressed IGF-I and induced Waf1 gene expression, demonstrating the requirement for an alpha, beta-unsaturated carbonyl for regulation of the two genes. The dione compound 4-cyclopentene-1,3-dione, which has two potentially reactive carbons rather than one, was considerably more potent than 2-cyclopentene-1-one in repressing IGF-I gene expression (IC50 = 30 microM for 4-cyclopentene-1,3-dione as compared with 167 microM for 2-cyclopentene-1-one). Additional results indicated that diethyl maleate, which has two alpha,beta-unsaturated carbonyls in a non-cyclic configuration, also repressed IGF-I gene expression (IC50 = 214 microM) and induced Waf1 gene expression, indicating that the cyclic structure is not required for either effect.
环戊烯酮前列腺素（PGA和PGJ系列）抑制细胞生长和致瘤性的分子途径目前尚不清楚。这些细胞反应可能是由生长相关基因和应激诱导基因的特定调控引起的。我们测试了多种前列腺素调节C6大鼠胶质瘤细胞中胰岛素样生长因子-I（IGF-I）和Waf1基因表达的能力。前列腺素（按效力顺序）PGJ2 > PGA1 > PGA2，约PGD2 >> PGE2均显著抑制IGF-I基因表达。除PGE2外，抑制IGF-I的相同前列腺素也诱导Waf1基因表达。然而，诱导Waf1的效力顺序与抑制IGF-I的顺序不同：PGA2 > PGA1 ≈ PGJ2 > PGD2。前列腺素在调节IGF-I和Waf1基因表达方面效力顺序不同，这表明可能涉及不同的细胞内信号来调节这两个基因。用N-乙酰-L-半胱氨酸预处理细胞以增加谷胱甘肽水平，可减弱PGA2对IGF-I和Waf1基因表达的影响。相反，用丁硫氨酸亚砜胺预处理耗尽细胞内谷胱甘肽池，则增强了PGA2对这两个基因表达的影响。这些结果表明，与谷胱甘肽结合可阻止PGA2对基因表达的调节。我们还测试了几种含有五元环系统的更简单化合物对IGF-I和Waf1基因表达的影响。2-环戊烯-1-酮可抑制IGF-I并诱导Waf1基因表达，而环戊烯或环戊烷则无此作用，这表明调节这两个基因需要α,β-不饱和羰基。二酮化合物4-环戊烯-1,3-二酮有两个而非一个潜在的反应性碳，在抑制IGF-I基因表达方面比2-环戊烯-1-酮效力强得多（4-环戊烯-1,3-二酮的IC50 = 30 μM，而2-环戊烯-1-酮为167 μM）。其他结果表明，在非环状结构中具有两个α,β-不饱和羰基的马来酸二乙酯也抑制IGF-I基因表达（IC50 = 214 μM）并诱导Waf1基因表达，这表明两种作用均不需要环状结构。
