15-deoxy-delta(12-14)-prostaglandin-j2 and Mouth-Neoplasms

Antineoplastic properties of cyclopentenone 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) involve peroxisome proliferator-activated receptor gamma (PPARgamma) dependent and independent mechanisms. We recently reported that 15d-PGJ2 inhibits cell growth and induces apoptosis in human oral squamous cell carcinoma (SCC) partly independent of PPARgamma activation. Given the importance of epidermal growth factor receptor (EGFR) as a therapeutic target in head and neck SCC, we addressed the effects of 15d-PGJ2 on EGFR expression. 15d-PGJ2, but not other PPARgamma ligands, abrogated EGFR protein expression in oral SCC cells. 15d-PGJ2 also decreased EGFR mRNA, indicating downmodulation at the transcriptional level. Moreover, treatment with 9,10-dihydro-15d-PGJ2, a 15d-PGJ2 analog lacking the reactive carbonyl group, failed to effect EGFR expression. These findings provide evidence for EGFR downregulation in oral SCC cells through a novel anticancer effect of 15d-PGJ2 that is attributed to the reactive cyclopentenone ring system.

Topics: Carcinoma, Squamous Cell; Cell Line, Tumor; Cyclopentanes; ErbB Receptors; Humans; Mouth Neoplasms; Prostaglandin D2; Receptors, Cytoplasmic and Nuclear; Transcription Factors

15-deoxy-Delta(12,14)-prostaglandin J(2) (15-d-PGJ(2)) and troglitazone have been shown to induce apoptosis in several carcinoma cell lines. However, apoptotic signaling pathways of these agents are poorly understood. We tested the hypothesis that peroxisome proliferator-activated receptor-gamma ligands such as these two agents will induce caspase-mediated apoptosis in human oral squamous cell carcinomas (SCC). Treatment of these cell lines with 15-d-PGJ(2) or troglitazone decreased cell viability in a time- and dose-dependent manner. 15-d-PGJ(2), but not troglitazone, induced apoptosis, and this effect was time-dependent. Exposure of cells to 20 micro M of 15-d-PGJ(2) initiated early cytochrome c release, followed by late caspase activation. Furthermore, co-treatment with caspase inhibitors such as Z-VAD-FMK or Z-DEVD-FMK of oral SCC cells that had been treated with 20 micro M of 15-d-PGJ(2) blocked apoptosis. Our study demonstrates that treatment with 15-d-PGJ(2), but not troglitazone, induces apoptosis in human SCC cell lines, and 15-d-PGJ(2) appears to work through cytochrome c release and caspase activation.

Topics: Amino Acid Chloromethyl Ketones; Analysis of Variance; Antineoplastic Agents; Apoptosis; Carcinoma, Squamous Cell; Caspase Inhibitors; Caspases; Cell Survival; Chromans; Cysteine Proteinase Inhibitors; Cytochrome c Group; Dose-Response Relationship, Drug; Enzyme Activation; Humans; Immunologic Factors; Mouth Neoplasms; Oligopeptides; Prostaglandin D2; Signal Transduction; Thiazoles; Thiazolidinediones; Time Factors; Troglitazone; Tumor Cells, Cultured

Activation of peroxisome proliferator-activated receptor gamma (PPARgamma) has been linked to induction of differentiation, cell growth inhibition and apoptosis in several types of human cancer. However, the possible effects of PPARgamma agonists on human oral squamous cell carcinoma have not yet been reported. In this study, treatment with 15-deoxy-Delta(12,14)-PGJ(2) (15-PGJ(2)), a natural PPARgamma ligand, induced a significant reduction of oral squamous cell carcinoma cell growth, which was mainly attributed to upregulation of apoptosis. Interestingly, rosiglitazone and ciglitazone, two members of the thiazolidinedione family of PPARgamma activators, did not exert a growth inhibitory effect. Given the critical role that the oncogene signal transducer and activator of transcription 3 (Stat3) plays in head and neck carcinogenesis, its potential regulation by PPARgamma ligands was also examined. Treatment of oral squamous cell carcinoma cells with 15-PGJ(2) induced an initial reduction and eventual elimination of both phosphorylated and unphosphorylated Stat3 protein levels. In contrast, other PPARgamma did not induce similar effects. Our results provide the first evidence of significant antineoplastic effects of 15-PGJ(2) on human oral squamous cell carcinoma cells, which may be related to downmodulation of Stat3 and are at least partly mediated through PPARgamma-independent events.

Topics: Apoptosis; Blotting, Western; Carcinoma, Squamous Cell; Cell Cycle; Cell Division; DNA Primers; DNA-Binding Proteins; Down-Regulation; Humans; Immunoenzyme Techniques; Immunologic Factors; Mouth Neoplasms; Phosphorylation; Prostaglandin D2; Receptors, Cytoplasmic and Nuclear; Reverse Transcriptase Polymerase Chain Reaction; STAT3 Transcription Factor; Thiazoles; Thiazolidinediones; Trans-Activators; Transcription Factors; Tumor Cells, Cultured