Effects of cyclopentenone prostaglandins and related compounds on insulin-like growth factor-I and Waf1 gene expression

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) PGJ(2) > PGA(1) > PGA(2) approximate to PGD(2) >> PGE(2) all significantly repressed IGF-I gene expression. With the exception of PGE(2), 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: PGA(2) > PGA(1) approximate to PGJ(2) > PGD(2). 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 PGA(2) on IGF-I and Waf1 gene expression. Conversely, depletion of the intracellular glutathione pool by pretreatment with buthionine sulfoximine potentiated the effect of PGA(2) on the expression of both genes. These results suggest that conjugation with glutathione prevents the regulation of gene expression by PGA(2). 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 cyclopentanone 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 3-cyclopentene-1,3-dione, which has two potentially reactive carbons rather than one, was considerably more potent than 2-cyclopenten-1-one in repressing IGF-I gene expression (IC50 = 30 mu M for 4-cyclopentene-1,3-dione as compared with 167 mu M for 2-cyclopenten-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 mu M) and induced Waf1 gene expression, indicating that the cyclic structure is not required for either effect. (C) 1998 Elsevier Science B.V.