prostaglandin-d2 and Mouth-Neoplasms

Peroxisome proliferator-activated receptor-gamma (PPAR-γ) activators have anti-cancer effects. Our objective was to determine the effect of PPAR-γ ligands 15-deoxy-D. NA and CA9-22 cells were treated in vitro with 15-PGJ. MTT assays demonstrated dose-dependent decreases after 15-PGJ. Our results suggest these agents, in addition to activating PPAR-γ, can downregulate NF-κB and potentiate apoptosis in oral cancer cells.

Topics: Carcinoma, Squamous Cell; Cell Line; Humans; Mouth Neoplasms; PPAR gamma; Prostaglandin D2

Upper aerodigestive cancer is an aggressive malignancy with relatively stagnant long-term survival rates over 20 yr. Recent studies have demonstrated that exploitation of PPARγ pathways may be a novel therapy for cancer and its prevention. We tested whether PPARγ is expressed and inducible in aerodigestive carcinoma cells and whether it is present in human upper aerodigestive tumors. Human oral cancer CA-9-22 and NA cell lines were treated with the PPAR activators eicosatetraynoic acid (ETYA), 15-deoxy-δ- 12,14-prostaglandin J2 (PG-J2), and the thiazolidinedione, ciglitazone, and evaluated for their ability to functionally activate PPARγ luciferase reporter gene constructs. Cellular proliferation and clonogenic potential after PPARγ ligand treatment were also evaluated. Aerodigestive cancer specimens and normal tissues were evaluated for PPARγ expression on gene expression profiling and immunoblotting. Functional activation of PPARγ reporter gene constructs and increases in PPARγ protein were confirmed in the nuclear compartment after PPARγ ligand treatment. Significant decreases in cell proliferation and clonogenic potential resulted from treatment. Lipid accumulation was induced by PPARγ activator treatment. 75% of tumor specimens and 100% of normal control tissues expressed PPARγ RNA, and PPARγ protein was confirmed in 66% of tumor specimens analyzed by immunoblotting. We conclude PPARγ can be functionally activated in upper aerodigestive cancer and that its activation downregulates several features of the neoplastic phenotype. PPARγ expression in human upper aerodigestive tract tumors and normal cells potentially legitimizes it as a novel intervention target in this disease. © 2016 Wiley Periodicals, Inc.

Topics: Antineoplastic Agents; Arachidonic Acids; Cell Line; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Head and Neck Neoplasms; Humans; Lipid Metabolism; Mouth; Mouth Neoplasms; PPAR gamma; Prostaglandin D2; Thiazolidinediones

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

Cyclopentenone 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) exerts antineoplastic effects on various types of human cancer. We recently showed that treatment with 15d-PGJ(2) induces apoptosis accompanied by downregulation of the oncogenic signal transducer and activator of transcription 3 (Stat3) signalling in human oral squamous cell carcinoma (SCC) cells. The current study examines the effects of 15d-PGJ(2) on the epidermal growth factor receptor (EGFR) and Janus Kinase (JAK)-mediated signalling pathways. Inhibition of Stat3 by 15d-PGJ(2) was abolished by exogenous stimulation with transforming growth factor alpha (TGF-alpha), but not interleukin 6 (IL-6), supporting a selective effect of 15d-PGJ(2) on IL-6-mediated signalling. Importantly, 15d-PGJ(2) selectively abrogated constitutive and IL-6-mediated JAK phosphorylation without affecting EGFR-activated levels. Moreover, the inhibitory effect of 15d-PGJ(2) on JAK signalling required the reactive alpha,beta-unsaturated carbon within the cyclopentenone ring. Targeting of JAK signalling using a specific JAK inhibitor also abolished Stat3 phosphorylation and resulted in apoptosis in oral SCC cells. Our findings provide the first evidence for 15d-PGJ(2)-mediated downregulation of constitutive and IL-6-induced JAK signalling in cancer and support that JAK inhibition and suppression of EGFR-independent Stat3 activation by 15d-PGJ(2) represent a promising approach for induction of apoptosis in oral SCC cells.

Topics: Apoptosis; Carcinoma, Squamous Cell; Cell Division; Cell Line, Tumor; ErbB Receptors; Humans; Interleukin-6; Janus Kinase 1; Mouth Neoplasms; Prostaglandin D2; Protein-Tyrosine Kinases; Signal Transduction

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

Four cyclopentenone prostaglandins (CPPGs) and PGE2 caused significant dose-dependent inhibition in growth of human oral squamous carcinoma cells (SCC-15). The rank order of their potency was PGJ2>PGA1>16, 16-dimethyl PGA1>PGA2>PGE2. In a follow-up experiment it was found that the mean per cent inhibition in cell growth by PGJ2 and delta12-PGJ2 at 10(-5) M was 61.22 and 63.81, while that of 5-fluorouracil and methotrexate was 36.67 and 38.86, respectively. delta12-PGJ2 and PGJ2 induced significant dose-dependent inhibition in nuclear DNA synthesis (i.e. cell proliferation). Combining vitamin E succinate with lower concentrations of CPPGs enhanced significantly their inhibitory effect on nuclear DNA synthesis of cancer cells.

Topics: Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Division; Dinoprostone; Fluorouracil; Humans; Methotrexate; Mouth Neoplasms; Prostaglandin D2; Prostaglandins A; Prostaglandins A, Synthetic; Prostaglandins, Synthetic; Tocopherols; Tumor Cells, Cultured; Vitamin E

Previous studies have shown that prostaglandin E2 (PGE2) and vitamin E succinate can act in an additive manner to inhibit the proliferation of human oral squamous carcinoma cells (SCC-25). The initial studies on the additive anticancer activity of PGE2 and vitamin E succinate have been extended to include antineoplastic PGs, delta 12-PGJ2 and PGJ2. Treatment of oral squamous carcinoma cells (SCC-15) with delta 12-PGJ2, PGJ2, and vitamin E succinate, individually, caused significant concentration-dependent inhibition of cell proliferation to various degrees. PGJ2 was most potent and caused an inhibition that corresponded to 85.55% at 10(-5) M. Addition of 1 microM of vitamin E succinate to delta 12-PGJ2 or PGJ2 resulted in a significant increase in the inhibitory potency of the lower concentrations of the two PGs. These results suggest a novel role for a mixture of PGs and vitamin E as potent antitumor proliferative agents.

Topics: Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Division; Dinoprostone; Drug Synergism; Humans; Male; Middle Aged; Mouth Neoplasms; Prostaglandin D2; Prostaglandins; Tocopherols; Vitamin E