prostaglandin-d2 and Esophageal-Neoplasms

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a member of the nuclear hormone receptor superfamily, is involved in suppressing the growth of several tumors. We showed that PPAR-gamma is expressed in Barrett's adenocarcinoma cell lines and inhibited the growth of these lines through the induction of G1 cell cycle arrest and apoptosis. We examined PPAR-gamma expression in human esophageal squamous cell carcinoma (SCC) in vitro and in vivo and investigated whether PPAR-gamma ligands affect the proliferation and apoptosis of human SCC cell lines. Biopsy specimens (n=46) obtained from human SCC of the esophagus were stained using a monoclonal antibody against human PPAR-gamma. We assessed the effects of PPAR-gamma ligands on the growth of SCC cells by adding 15-deoxy prostaglandin J2 (15d-PGJ2), or troglitazone to six human esophageal SCC cell lines (TE-1, TE-2, TE-3, TE-5, TE-8, and TE-9). Immunohistochemical staining showed that 34 of 46 (73.9%) SCC of the esophagus expressed PPAR-gamma. All SCC cell lines expressed PPAR-gamma mRNA and protein, especially when poorly differentiated (TE-2, TE-5, and TE-9). The PPAR-gamma ligands significantly and dose-dependently inhibited the proliferation of SCC lines, except for well-differentiated TE-1 and TE-3. Apoptosis was induced by 15d-PGJ2 (10 microM) in all tested SCC lines except TE-1, whereas troglitazone (50 microM) was marginally effective in only the TE-2 and TE-3 cell lines. The present findings suggest that PPAR-gamma could be a therapeutic target for treating squamous cell carcinoma of the esophagus, possibly through the induction of apoptosis.

Topics: Antibodies, Monoclonal; Apoptosis; Barrett Esophagus; Biopsy; Bisbenzimidazole; Blotting, Western; Carcinoma, Squamous Cell; Caspase 3; Caspases; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Chromans; Dose-Response Relationship, Drug; Esophageal Neoplasms; G1 Phase; Humans; Immunohistochemistry; Ligands; PPAR gamma; Prostaglandin D2; Reverse Transcriptase Polymerase Chain Reaction; RNA; RNA, Messenger; Thiazolidinediones; Thymidine; Troglitazone

Peroxisome proliferator-activated receptor gamma (PPAR-gamma), a member of the nuclear hormone receptor superfamily, is involved in suppression of growth of several types of tumors such as liposarcoma, breast cancer, prostate cancer, and colon cancer, possibly through induction of cell cycle arrest and/or apoptosis. In this study, we demonstrated expression of PPAR-gamma mRNA and protein in human esophageal carcinoma cells. Expression of PPAR-gamma protein was higher in an adenocarcinoma cell line (TE-7 cells) than in a squamous cell carcinoma cell line (TE-1 cells). PPAR-gamma ligands such as 15-deoxy-Delta12,14-prostaglandin J2 and troglitazone significantly inhibited the growth of TE-7 cells but had less or no effect on growth of TE-1 cells. 15d-PGJ2 and troglitazone induced apoptosis in TE-7 cells but not in TE-1 cells. Troglitazone caused G1 cell cycle arrest and reduced ornithine decarboxylase activity (ODC) in TE-7 cells but not in TE-1 cells. Inhibition by PPAR-gamma ligands of growth of esophageal adenocarcinoma cells may thus be due to induction of apoptosis, G1 cell cycle arrest and reduction of ODC activity.

Topics: Adenocarcinoma; Antineoplastic Agents; Apoptosis; Blotting, Western; Carcinoma, Squamous Cell; Cell Cycle; Cell Division; Chromans; DNA Primers; Esophageal Neoplasms; Flow Cytometry; Humans; Immunologic Factors; Ligands; Ornithine Decarboxylase; Prostaglandin D2; Receptors, Cytoplasmic and Nuclear; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tetrazolium Salts; Thiazoles; Thiazolidinediones; Thymidine; Transcription Factors; Troglitazone; Tumor Cells, Cultured

delta 12-PGJ2, one of the cyclopentenone prostaglandins and the ultimate metabolite of prostaglandin D2, has been reported to have potent antiproliferative activity on various tumor cells in vitro and in vivo. In this study, the combined effect of delta 12-PGJ2 and hyperthermia on six established cell lines of human esophageal carcinoma (SGF series) was analyzed by an in vitro assay, and the degree of apoptosis induced by this combination was examined to clarify the mechanism of supra-additive effects. In five SGF cell lines, except SGF-7 cells, combination therapy with delta 12-PGJ2 and hyperthermia showed synergistic antiproliferative effects. The supra-additive combined effect of delta 12-PGJ2 and hyperthermia on esophageal cancer cells is attributed to the synergistic induction of apoptosis. delta 12-PGJ2 induced G1 accumulation and apoptosis was induced by delta 12-PGJ2 from G1 phase. Hyperthermia induced G1 accumulation and apoptosis was induced by hyperthermia during all cell phases. Both augmented G1 arrest followed by G1 phase-selective induction of apoptosis and increased apoptotic induction without cell-cycle specificity are responsible for the synergism of combined treatment with delta 12-PGJ2 and hyperthermia.

Topics: Adult; Aged; Apoptosis; Cell Division; Combined Modality Therapy; Esophageal Neoplasms; Humans; Hyperthermia, Induced; Male; Middle Aged; Prostaglandin D2; Tumor Cells, Cultured