The effect of fenofibrate, a ligand of peroxisome proliferator-activated receptor (PPAR) alpha, on the growth and metastatic potential of Bomirski hamster melanoma s.c. tumors, pigmented line (BHM Ma) was investigated in vivo. RT-PCR and Western-blot analyses revealed the presence of mRNA and protein of PPAR alpha in BHM Ma cells. The animals treated orally with fenofibrate developed significantly fewer metastatic foci in the lungs, as compared to the control group; however, primary tumor growth remained unaltered. This observation is interesting in respect of the potential use of fenofibrate in melanoma chemoprevention.
The expression and activity of cystathionine γ-lyase (CST) and 3-mercaptopyruvate sulfurtransferase (MPST) were investigated in the human neoplastic cells lines: astrocytoma U373, neuroblastoma SH-SY5Y, melanoma A375, and melanoma WM35. Gene expression analysis demonstrated that the investigated neoplastic cells showed the expression of MPST and what is particularly interesting, the expression of CST. The presence of CST in these cells was confirmed using RT-PCR and western blot analysis. However, in U373 cells, a very low activity of CST was detected. In all the investigated cell lines, the activity of MPST was higher than that of CST, which suggests that in these cells, the main pathway of sulfane sulfur formation is the MPST-catalyzed reaction. RP-HPLC analysis showed a large disparity between the level of cystathionine and GSH in the investigated neoplastic cells. In SH-SY5Y cells, the low level of GSH and low GSH/GSSG ratio corresponded with the highest CST activity. Further investigations could aim at verifying whether the stimulation of CST, at the level of protein or gene expression, could change the proliferation of neoplastic cells.
The peroxisome proliferator-activated receptor gamma (PPARgamma) is a member of the nuclear receptor family of ligand-activated transcription factors. PPARgamma ligands have been shown to inhibit the growth of cells from different cancer lineages. This study was designed to evaluate the effects of PPARgamma receptor activation in human melanoma cell lines. The effects of its expression and activation on cell proliferation and apoptosis in human melanoma cell lines (early stage cancer [WM35] and metastatic tumour [A375]) were investigated. Reverse transcription-polymerase chain reaction and Western blot analysis showed that both human melanoma cell lines expressed PPARgamma mRNA and protein. Treatment of cells transfected with the luciferase gene ligated to PPAR response element constructed promoter showed that ciglitazone and prostaglandin J2 (PGJ2), selective ligands for PPARgamma, increased the luciferase activity, proving the induction of the PPARgamma reporter gene. Ciglitazone and PGJ2 inhibited melanoma cell proliferation in a dose-dependent manner. Analysis of the cellular morphology and apoptosis assayed by fluorescence microscopy after incubation of A375 cells with 10 micro M ciglitazone for 24 h indicated that this ligand not only inhibited cell proliferation but also induced apoptosis.
Melanoma represents one of the most rapidly metastasizing, hence deadly tumors due to its high proliferation rate and invasiveness, characteristics of undifferentiated embryonic tissues. Given the absence of effective therapy for metastatic melanoma, understanding more fully the molecular mechanisms underlying melanocyte differentiation may provide opportunities for novel therapeutic intervention. Here we show that in mouse melanoma S91 cells activation of the peroxisome proliferator activated receptor (PPAR) gamma induces events resembling differentiation, such as growth arrest accompanied by apoptosis, spindle morphology and enhanced tyrosinase expression. These events are preceded by an initial transient increase in expression from the Microphthalmia-associated transcription factor gene, (MITF) promoter, whereas exposure to a PPAR gamma ligand- ciglitazone that exceeds 8 h, causes a gradual decrease of MITF, until by 48 h MITF expression is substantially reduced. Beta-catenin, an MITF transcriptional activator, shows a similar pattern of decline during ciglitazone treatment, consistent with previous reports that activated PPAR gamma inhibits the Wnt/beta-catenin pathway through induction of beta-catenin proteasomal degradation. We suggest that the PPAR gamma-mediated beta-catenin down-regulation is likely to be responsible for changes in MITF levels. The data suggest that PPAR gamma, besides its well-established role in mesenchymal cell differentiation towards adipocytes, might regulate differentiation in the melanocytic lineage.
Peroxisome proliferator-activated receptors-g (PPARg) are ligand-inducible transcription factors of the nuclear hormone receptor superfamily. We examined the effect of PPARg activation on the generation of vascular endothelial growth factor (VEGF), one of the major angiogenic agents. Rat vascular smooth muscle cells (VSMC) and murine macrophages RAW264.7 were incubated for 24 h with PPARg activators: prostaglandin J 2 and ciglitazone. PPARg were expressed in VSMC and RAW cells and their activity was upregulated in the presence of PGJ 2 and ciglitazone. Incubation of the cells with PPARg activators significantly augmented the release of VEGF protein into the media, both in resting and in IL-1b-or LPS-stimulated cultures. The higher protein generation was connected with the increased expression of mRNA and Vol.
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