15-deoxy-delta(12-14)-prostaglandin-j2 and Melanoma

The PPAR-gamma ligands, 15-deoxy-Delta(12,14)-prostaglandin J(2) and ciglitazone, and the PPAR-alpha ligand, WY-14643, were examined for their effects on proliferation and apoptosis of A375 melanoma, DU145 and PC3 prostate cancer, and MB-MDA-231 breast cancer. While 15-deoxy-Delta(12,14)-prostaglandin J(2) inhibited proliferation of A375 melanoma, ciglitazone was inactive against this and the other cell lines. Restriction of specific amino acids known to inhibit proliferation and induce apoptosis sensitized all cell lines to ciglitazone, and the combined effects were greater than the individual effects of either treatment. WY-14643 alone or in combination with amino acid deprivation was inactive. Normal fibroblasts were resistant to the treatments.

Topics: Amino Acids; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Female; Humans; Hypoglycemic Agents; Immunologic Factors; Ligands; Male; Melanoma; Methionine; Phenylalanine; PPAR gamma; Prostaglandin D2; Prostatic Neoplasms; Thiazolidinediones; Tyrosine

Peroxisome proliferator-activated receptor gamma is a member of the nuclear receptor superfamily involved in adipocyte differentiation and glucose homeostasis. There is evidence that peroxisome proliferator-activated receptor gamma may also act as a tumor suppressor. Here, we demonstrate expression of peroxisome proliferator-activated receptor gamma in benign melanocytic naevi, different variants of primary cutaneous melanomas, and melanoma metastases. Peroxisome proliferator-activated receptor gamma protein and peroxisome proliferator-activated receptor gamma1 mRNA were also detected in human melanoma cell lines. The peroxisome proliferator-activated receptor gamma specific agonists 15-deoxy-Delta12,14-prostaglandin J2, troglitazone, and rosiglitazone dose-dependently inhibited cell proliferation in four melanoma cell lines, whereas a specific agonist of peroxisome proliferator-activated receptor alpha had no such effect. At a concentration of 50 microM rosiglitazone, the most potent peroxisome proliferator-activated receptor gamma agonist tested suppressed cell growth by approximately 90%. Apoptosis could be induced in melanoma cell lines by incubation with tumor-necrosis-factor-related apoptosis-inducing ligand. In contrast, the growth inhibitory effect of peroxisome proliferator-activated receptor gamma activation was independent of apoptosis and seemed to occur primarily through induction of cell cycle arrest. Our data indicate that melanoma cell growth may be modulated through peroxisome proliferator-activated receptor gamma.

Topics: Antineoplastic Agents; Apoptosis; Cell Division; Chromans; Dose-Response Relationship, Drug; Fibrinolytic Agents; Gene Expression Regulation, Neoplastic; Humans; Immunologic Factors; Melanoma; Prostaglandin D2; Receptors, Cytoplasmic and Nuclear; RNA, Messenger; Rosiglitazone; Skin Neoplasms; Thiazoles; Thiazolidinediones; Transcription Factors; Troglitazone; Tumor Cells, Cultured