prostaglandin-d2 and Uterine-Neoplasms

Peroxisome proliferator-activated receptor (PPAR) gamma is an important signaling molecule in cells of mesenchymal origin, inducing differentiation and regulating cell proliferation in several cell types such as vascular smooth muscle cells. Leiomyomas arise from smooth muscle cells of the uterine myometrium with an incidence rate as high as 70% in women of reproductive age. PPAR signaling has not been characterized in these tumors, although prostaglandins, natural PPAR ligands, are known effectors of key biological functions in the normal myometrium. Leiomyomas and tumor-derived cells isolated from a rat model for this disease were characterized by Western analysis and found to express all three PPAR isoforms, suggesting that signaling pathways mediated by these receptors were intact in this tumor type. In vitro experiments with a leiomyoma-derived cell line demonstrated that the pan-PPAR ligand cis-4,7,10,13,16,19-docosahexaenoic acid and PPARgamma-specific ligands 15-deoxy-delta(12,14)-prostaglandin J(2), troglitazone, and ciglitazone inhibited 17beta-estradiol-stimulated cell proliferation. This inhibitory effect was not observed with PPARalpha- or PPARbeta-specific ligands. Although both PPAR and estrogen receptor (ER) signaling pathways were intact in leiomyoma cells, in addition to growth inhibition, stimulation of PPARgamma signaling also inhibited ER-mediated gene expression. Human leiomyomas were also found to express all three PPAR isoforms, and primary cultures of these cells were sensitive to the inhibitory effects of PPARgamma ligands. These results suggest that in uterine leiomyomas PPARgamma activation is growth inhibitory and that this inhibition is mediated at least in part by negative cross-talk between ER and PPAR signaling pathways.

Topics: Animals; Cell Division; Chromans; Docosahexaenoic Acids; Estradiol; Female; Humans; Leiomyoma; Ligands; Prostaglandin D2; Protein Isoforms; Rats; Receptors, Cytoplasmic and Nuclear; Receptors, Estrogen; Signal Transduction; Thiazoles; Thiazolidinediones; Transcription Factors; Troglitazone; Tumor Cells, Cultured; Uterine Neoplasms

Apoptosis has been described in placental (trophoblast) tissues during both normal and abnormal pregnancies. We have studied the effects of the cyclopentenone prostaglandins (PGs) on trophoblast cell death using JEG3 choriocarcinoma cells. PGJ(2), Delta(12)PGJ(2), and 15-deoxy-Delta(12,14)-PGJ(2) (15dPGJ(2)) (10 microM) significantly reduced mitochondrial activity (MTT assay) over 16 h by 17.4 +/- 4.7%, 28 +/- 9.3%, and 62.5 +/- 2.8%, respectively (mean +/- sem), while PGA(2) and PGD(2) had no effect. The synthetic PPAR-gamma ligand ciglitizone (12.5 microM) had a potency similar to 15dPGJ(2) (69 +/- 3% reduction). Morphological examination of cultures treated with PGJ(2) and its derivatives revealed the presence of numerous cells with dense, pyknotic nuclei, a hallmark of apoptosis. FACS analysis revealed an abundance (approximately 40%) of apoptotic cells after 16-h treatment with 15dPGJ(2) (10 microM). The caspase inhibitor ZVAD-fmk (5 microM) significantly diminished the apoptotic effects of Delta(12)PGJ(2) and 15dPGJ(2). JEG3 cells expressed PPAR-gamma mRNA by Northern analysis. These novel findings imply a role for PPAR-gamma ligands in various processes associated with pregnancy and parturition.

Topics: Amino Acid Chloromethyl Ketones; Apoptosis; Choriocarcinoma; Dinoprost; Female; Humans; Labor, Obstetric; Mitochondria; Nuclear Proteins; Pregnancy; Prostaglandin D2; Prostaglandins A; Receptors, Cytoplasmic and Nuclear; RNA, Messenger; Transcription Factors; Transcription, Genetic; Tumor Cells, Cultured; Uterine Neoplasms

The effects of tumor necrosis factor (TNF) and cyclopentenone prostaglandins (PGA2 and delta 12-PGJ2), singly and in combination, against proliferation in three human gynecologic tumor cell lines (HeLa S3, HHUA, and CAOV-3) were examined in vitro. The HeLa S3 and CAOV-3 cells were unresponsive to TNF, and the HHUA cells exhibited a minimal degree of responsiveness to TNF. The HeLa S3 and HHUA cells were responsive dose-dependently to PGA2, and the CAOV-3 cells were slightly responsive to PGA2. All three cell lines were highly responsive to delta 12-PGJ2. The synergistic antiproliferative effect of TNF and delta 12-PGJ2 appeared in all three cell lines. Pretreatment with delta 12-PGJ2 enhanced the effectiveness of TNF in these cell lines, but not vice versa. A synergistic interaction between TNF and PGA2 was absent in these three cell lines. These results suggest that a combined treatment with TNF and delta 12-PGJ2 could provide a new approach to obtaining increased responses in clinical trials.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cell Division; Drug Synergism; Female; HeLa Cells; Humans; Ovarian Neoplasms; Prostaglandin D2; Prostaglandins A; Prostaglandins, Synthetic; Recombinant Proteins; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha; Uterine Neoplasms

Effects of prostaglandin F2 alpha, E2, D2 and J2 on the DNA and RNA contents of a human endometrial cancer cell lines (SNG and Ishikawa) were studied using flow cytometry. Cytotoxic effects of various prostaglandins on SNG and Ishikawa cell lines were examined and PG J2 and PG D2 were found most active. Among other prostaglandins PG E2 showed a comparable inhibitory activity to cellular growth but PG F2 alpha didn't. In SNG and Ishikawa cell lines after RNase treatment, PG J2, PG D2 and PG E2 caused a decrease of the S-phase and G2 + M-phase cell population in cell cycle. On the other hand, PG F2 alpha caused a increase of the S-phase cell population in cell cycle PG J2, PG D2 and PG E2 after DNase treatment caused a decrease of the relative RNA content in both of cell lines. On the other hand, PG F2 alpha caused a increase of the relative RNA content. It is a noteworthy that PG J2 and PG D2 were remarkably recognized delay of doubling time and decrease of survival fraction under the time and dose dependence. These effects occur not only by direct lethal influence of the prostaglandins, but also by substantially inhibit RNA and DNA synthesis with a delay of the cell cycle. These results might be suggested a role for prostaglandin J2 and D2 in the regulation of growth of endometrial adenocarcinoma cells.

Topics: Adenocarcinoma; Cell Cycle; Cell Division; Cells, Cultured; Colony-Forming Units Assay; Dinoprost; Dinoprostone; Female; Flow Cytometry; Humans; Prostaglandin D2; Prostaglandins D; Prostaglandins E; Prostaglandins F; Tumor Stem Cell Assay; Uterine Neoplasms