17 research outputs found
PPARβ activation inhibits melanoma cell proliferation involving repression of the Wilms’ tumour suppressor WT1
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that strongly influence molecular signalling in normal and cancer cells. Although increasing evidence suggests a role of PPARs in skin carcinogenesis, only expression of PPARγ has been investigated in human melanoma tissues. Activation of PPARα has been shown to inhibit the metastatic potential, whereas stimulation of PPARγ decreased melanoma cell proliferation. We show here that the third member of the PPAR family, PPARβ/δ is expressed in human melanoma samples. Specific pharmacological activation of PPARβ using GW0742 or GW501516 in low concentrations inhibits proliferation of human and murine melanoma cells. Inhibition of proliferation is accompanied by decreased expression of the Wilms’ tumour suppressor 1 (WT1), which is implicated in melanoma proliferation. We demonstrate that PPARβ directly represses WT1 as (1) PPARβ activation represses WT1 promoter activity; (2) in chromatin immunoprecipitation and electrophoretic mobility shift assays, we identified a binding element for PPARβ in the WT1 promoter; (3) deletion of this binding element abolishes repression by PPARβ and (4) the WT1 downstream molecules nestin and zyxin are down-regulated upon PPARβ activation. Our findings elucidate a novel mechanism of signalling by ligands of PPARβ, which leads to suppression of melanoma cell growth through direct repression of WT1
Current and Future Drug Targets in Weight Management
Obesity will continue to be one of the leading causes of chronic disease unless the ongoing rise in the prevalence of this condition is reversed. Accumulating morbidity figures and a shortage of effective drugs have generated substantial research activity with several molecular targets being investigated. However, pharmacological modulation of body weight is extremely complex, since it is essentially a battle against one of the strongest human instincts and highly efficient mechanisms of energy uptake and storage. This review provides an overview of the different molecular strategies intended to lower body weight or adipose tissue mass. Weight-loss drugs in development include molecules intended to reduce the absorption of lipids from the GI tract, various ways to limit food intake, and compounds that increase energy expenditure or reduce adipose tissue size. A number of new preparations, including combinations of the existing drugs topiramate plus phentermine, bupropion plus naltrexone, and the selective 5-HT2C agonist lorcaserin have recently been filed for approval. Behind these leading candidates are several other potentially promising compounds and combinations currently undergoing phase II and III testing. Some interesting targets further on the horizon are also discussed
PPAR-δ is repressed in Huntington's disease, is required for normal neuronal function and can be targeted therapeutically
Huntington’s disease (HD) is a progressive neurodegenerative disorder caused by a CAG-polyglutamine repeat expansion in the huntingtin (htt) gene. We found that peroxisome proliferator-activated receptor delta (PPARδ) interacts with htt and that mutant htt represses PPARδ-mediated transactivation. Increased PPARδ transactivation ameliorated mitochondrial dysfunction and improved cell survival of HD neurons. Expression of dominant-negative PPARδ in CNS was sufficient to induce motor dysfunction, neurodegeneration, mitochondrial abnormalities, and transcriptional alterations that recapitulated HD-like phenotypes. Expression of dominant-negative PPARδ specifically in the striatum of medium spiny neurons in mice yielded HD-like motor phenotypes, accompanied by striatal neuron loss. In mouse models of HD, pharmacologic activation of PPAR δ, using the agonist KD3010, improved motor function, reduced neurodegeneration, and increased survival. PPAR δ activation also reduced htt-induced neurotoxicity in vitro and in medium spiny-like neurons generated from human HD stem cells, indicating that PPAR δ activation may be beneficial in individuals with HD and related disorders
Resistance to type 2 diabetes mellitus: a matter of hormesis?
Type 2 diabetes mellitus is characterized by subclinical systemic inflammation and impaired regulation of blood glucose levels. Interestingly, impairment of glycemic control occurs despite substantial insulin secretion early in the course of this disease. Dysfunction of several organs (including pancreatic islets, liver, skeletal muscle, adipose tissue, gut, hypothalamus and the immune system) has been implicated in the pathogenesis of type 2 diabetes mellitus. However, diabetes-promoting lifestyle factors do not inevitably cause disease in all persons exposed. Hence, defense mechanisms must exist that can keep the detrimental influence of these risk factors at bay. Hormesis describes the phenomenon that exposure to a mild stressor confers resistance to subsequent, otherwise harmful, conditions of increased stress. This Review discusses the emerging concept that the effectiveness of an adaptive (hormetic) response to detrimental lifestyle factors determines the extent of protection from progression to type 2 diabetes mellitus. Further analysis of these protective hormetic responses at the molecular level should help to identify novel targets for preventive or therapeutic intervention in patients at risk of developing type 2 diabetes mellitus or those with overt disease.Journal ArticleResearch Support, Non-U.S. Gov'tReviewSCOPUS: ar.jinfo:eu-repo/semantics/publishe