prostaglandin-d2 and Skin-Neoplasms

The combined incidence of melanoma and non-melanoma skin cancer (NMSC) is greater than the incidence of all other malignancies in the US. Previously, we demonstrated that the endocannabinoid, arachidonoyl-ethanolamide (AEA), was a potent inducer of apoptosis in NMSC. The metabolism of AEA to the prostaglandin, PGD

Topics: Animals; Apoptosis; Caspase 3; Caspase 7; Cell Line, Tumor; Endoplasmic Reticulum Stress; Glutathione; Melanoma; Mice; Oxidative Stress; Prostaglandin D2; Skin Neoplasms; Thioredoxins

Aldo-keto reductase 1C3 (AKR1C3) is an enzyme involved in metabolizing prostaglandins (PGs) and sex hormones. It metabolizes PGD2 to 9α11β-PGF2 , diverting the spontaneous conversion of PGD2 to the PPARγ agonist, 15-Deoxy-Delta-12, 14-prostaglandin J2 (15d-PGJ2 ). AKR1C3 is overexpressed in various malignancies, suggesting a tumor promoting function. This work investigates AKR1C3 expression in human non-melanoma skin cancers, revealing overexpression in squamous cell carcinoma (SCC). Effects of AKR1C3 overexpression were then evaluated using three SCC cell lines. AKR1C3 was detected in all SCC cell lines and its expression was upregulated in response to its substrate, PGD2 . Although attenuating AKR1C3 expression in SCC cells by siRNA did not affect growth, treatment with PGD2 and its dehydration metabolite, 15d-PGJ2 , decreased SCC proliferation in a PPARγ-dependent manner. In addition, treatment with the PPARγ agonist pioglitazone profoundly inhibited SCC proliferation. Finally, we generated an SCC cell line that stably overexpressed AKR1C3 (SCC-AKR1C3). SCC-AKR1C3 metabolized PGD2 to 9α11β-PGF2 12-fold faster than the parent cell line and was protected from the antiproliferative effect mediated by PGD2 . This work suggests that PGD2 and its metabolite 15d-PGJ2 attenuate SCC proliferation in a PPARγ-dependent manner, therefore activation of PPARγ by agonists such as pioglitazone may benefit those at high risk of SCC.

Topics: 3-Hydroxysteroid Dehydrogenases; Aldo-Keto Reductase Family 1 Member C3; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Cells, Cultured; Gene Expression Regulation, Neoplastic; Humans; Hydroxyprostaglandin Dehydrogenases; PPAR gamma; Prostaglandin D2; Prostaglandins; RNA, Small Interfering; Skin; Skin Neoplasms; Up-Regulation

This study shows that prostaglandins in human FM55 melanoma cells and epidermal melanocytes are produced by COX-1. Prostaglandin production in FM55 melanoma cells was unrelated to that of melanin suggesting that the two processes can occur independently. Alpha-melanocyte-stimulating hormone, which had no effect on melanin production in FM55 cells, stimulated PGD(2) production in these cells without affecting PGE(2). While cAMP pathways may be involved in regulating PGD(2) production, our results suggest that alpha-MSH acts independently of cAMP, possibly by regulating the activity of lipocalin-type PGD synthase. This alpha-MSH-mediated effect may be associated with its role as an immune modulator.

Topics: alpha-MSH; Cell Line, Tumor; Cells, Cultured; Cyclic AMP; Cyclooxygenase 1; Humans; Intramolecular Oxidoreductases; Lipocalins; Melanins; Melanocytes; Melanoma; Prostaglandin D2; Prostaglandins D; Skin Neoplasms

Treatments for primary and metastatic melanomas are rarely effective. Even therapeutics such as retinoic acid (RA) that are successfully used to treat several other forms of cancer are ineffective. Recent evidence indicates that the antiproliferative effects of RA are mediated by the transcription factor SOX9 in human cancer cell lines. As we have previously shown that SOX9 is expressed in normal melanocytes, here we investigated SOX9 expression and function in human melanomas. Although SOX9 was expressed in normal human skin, it was increasingly downregulated as melanocytes progressed to the premalignant and then the malignant and metastatic states. Overexpression of SOX9 in both human and mouse melanoma cell lines induced cell cycle arrest by increasing p21 transcription and restored sensitivity to RA by downregulating expression of PRAME, a melanoma antigen. Furthermore, SOX9 overexpression in melanoma cell lines inhibited tumorigenicity both in mice and in a human ex vivo model of melanoma. Treatment of melanoma cell lines with PGD2 increased SOX9 expression and restored sensitivity to RA. Thus, combined treatment with PGD2 and RA substantially decreased tumor growth in human ex vivo and mouse in vivo models of melanoma. The results of our experiments targeting SOX9 provide insight into the pathophysiology of melanoma. Further, the effects of SOX9 on melanoma cell proliferation and RA sensitivity suggest the encouraging possibility of a noncytotoxic approach to the treatment of melanoma.

Topics: Animals; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p21; Down-Regulation; Humans; Melanoma; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Mice, Nude; Microphthalmia-Associated Transcription Factor; Nevus; Prostaglandin D2; Skin Neoplasms; SOX9 Transcription Factor; Tretinoin; Up-Regulation

Invariant NK T (iNKT) cells are a subset of innate/memory lymphocytes that recognize lipid Ags presented by CD1d-expressing APCs such as dendritic cells (DCs). Upon primary stimulation through their TCR, iNKT cells promptly produce large amounts of IFN-gamma and/or IL-4 that play critical roles in the regulation of innate and adaptive immune responses. To date, the role of environmental factors on iNKT cell functions has been poorly investigated. In this study, we addressed the question of whether PGD2, a potent eicosanoid lipid mediator involved in immune responses and inflammation, could be important in DC/iNKT cell cross-talk. We show that PGD2 dramatically reduced the production of IFN-gamma, but not IL-4, by iNKT cells in response to the superagonist alpha-galactosylceramide (alpha-GalCer) both in vitro and in vivo. This effect is mediated by the D prostanoid receptor 1 (DP1) expressed by DCs and iNKT cells and requires protein kinase A activation. We also report that PGD2 and BW245C (a selective DP1 agonist) reduce the protective effects of alpha-GalCer in B16F10-induced melanoma metastasis, an effect that depends on IFN-gamma production by iNKT cells. As a whole, these data reveal novel pathways regulating iNKT cell biologic functions and confirm the immunoregulatory roles of PGD2 on the innate response.

Topics: Animals; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Dendritic Cells; Hydantoins; Immunity, Innate; Interferon-gamma; Killer Cells, Natural; Lung Neoplasms; Melanoma, Experimental; Mice; Prostaglandin D2; Receptors, Prostaglandin; Skin Neoplasms; T-Lymphocytes

The effect of prostaglandins on the development of papillomas has been investigated in mice receiving prostaglandins E2 (PGE2) or the cyclopentenone 15-deoxy-delta(12,14)-PGJ2 (15dPGJ2) topically, using the 7,12-dimethylbenz[a]anthracene (DMBA)-induced tetradecanoylphorbol acetate (TPA)-promoted model of skin carcinogenesis. The presence of 15dPGJ2 during DMBA and TPA treatment inhibited apoptosis and increased the rate, number, size and vascularization of the papillomas, some of them progressing into carcinomas. Moreover, skin sections from mice treated for one week with DMBA and 15dPGJ2 showed a much reduced rate of apoptotic cells, and an enhanced expression of vascular epithelial growth factor when compared with animals receiving DMBA, with or without PGE2. The analysis of molecular events in the MCA3D keratinocyte cell line showed that 15dPGJ2 activated Ras and improved cell viability by inhibiting DMBA-dependent apoptosis. In addition to this, cell adhesion was impaired in MCA3D keratinocytes co-treated with 15dPGJ2 and DMBA, at the same time when the expression of cyclooxygenase-2 (COX-2) was observed under these conditions. These effects mediated by 15dPGJ2 might contribute to understand the role of COX-2 metabolites in carcinogenesis, leading to an increase of cell viability after mutagenic injury and therefore in the progression of tumors.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Administration, Topical; Animals; Apoptosis; Carcinogens; Cell Transformation, Neoplastic; Cyclooxygenase 2; Disease Progression; Drug Interactions; Female; Immunologic Factors; Keratinocytes; Mice; Papilloma; Prostaglandin D2; Skin Neoplasms

The novel synthetic oleanane triterpenoid CDDO (2-cyano-3, 12-dioxoolean-1, 9-dien-28-oic acid) can serve as a ligand for the peroxisome proliferator activator receptor-gamma (PPAR-gamma) and has been shown to inhibit cell proliferation, and to induce differentiation and apoptosis in tumor cell lines. Bexarotene is an RXR-selective retinoid that can induce apoptosis of mycosis fungoides (MF) and Sézary syndrome (SS) cells. Since the PPAR-gamma and RXR receptors can form heterodimers, we studied the effects of CDDO and its synergism with bexarotene on apoptosis in MF/SS cell lines (MJ, Hut78, and HH) and freshly isolated peripheral blood lymphocytes (PBL) from SS patients with circulating atypical T cells (CD4+CD26-). CDDO treatment at 1-5 microM for 48 h caused a concentration-dependent apoptosis in three MF/SS cell lines and patients' PBL compared to vehicle controls. Bexarotene augmented CDDO-induced apoptosis in these cells. PPAR-gamma was expressed but decreased by 47% in MJ, 42% in Hut78, and 77% in HH cells following CDDO treatment. The anti-apoptotic protein bcl-xL, but not bcl-2, was decreased by 69% in MJ, 31% in Hut78, and 59% in HH cells and caspase-3 was activated following CDDO treatment. Interestingly, the PPAR-gamma antagonist T007 did not block CDDO-induced apoptosis, and the more potent PPAR-gamma agonist rosiglitazone required much higher concentrations (>50 microM) than CDDO to induce apoptosis in MF/SS cells. In summary, CDDO induces apoptosis that is further enhanced by bexarotene and decreases the PPAR-gamma and bcl-xL proteins in MF/SS cells. CDDO's effects on MF/SS cells may be at least partly mediated through a PPAR-gamma-independent mechanism. Our findings suggest the rationale for further investigation of the clinical potential of CDDO, either alone or in combination with bexarotene for MF/SS patients.

Topics: Anticarcinogenic Agents; Apoptosis; Bexarotene; Cell Division; Cell Line, Tumor; Drug Synergism; Humans; Immunologic Factors; Ligands; Lymphocytes; Mycosis Fungoides; Nitric Oxide; Oleanolic Acid; Prostaglandin D2; Receptors, Cytoplasmic and Nuclear; Sezary Syndrome; Skin Neoplasms; Tetrahydronaphthalenes; Transcription Factors

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