PPARγ inhibits breast cancer progression by upregulating PTPRF expression.
18
Citation
0
Reference
10
Related Paper
Citation Trend
Abstract:
Peroxisome proliferator-activated receptor γ (PPARγ) regulates fatty acid storage and glucose metabolism. Recently, PPARγ has been reported to be involved in cancer. The present study reported a PPARγ consensus binding site (AGGTCA) in the ptprf promoter and identified a strong association between PPARγ and PTPRF expression, as well as their tumor suppressor roles in a v-Ha-Ras-induced model of breast cancer.The prognostic potential of PPARγ was assessed with a KM analysis of raw data from 3,951 breast cancer patients. The expression of PPARγ and PTPRF in the rat breast cancer cell lines was detected by Western blot and qPCR. The impact of PPARγ on cancer cell migration, invasion, and growth was confirmed using cell migration assay, transwell cell invasion assay, tri-dimensional soft agar culture, respectively. The binding of PPARγ with the ptprf promoter was then examined using electrophoretic mobility shift assay. The inhibitory effect of PPARγ on tumor growth was then examined in mouse tumor model in vivo.It was identified that PPARγ expression is lost in the aggressive v-Ha-Ras-induced breast cancer cell line FE1.2 but highly expressed in less malignant FE1.3 cells. Exogenous expression of PPARγ in FE1.2 cells (FE1.2-PPARγhi) resulted in a marked inhibition of proliferation compared with that in FE1.2-Vector control group. FE1.2-PPARγhi cells also exhibited reduced migration, invasion, and colony formation abilities compared with those of the controls. The PPARγ agonist rosiglitazone also suppressed the malignant properties of FE1.2 cells. Protein tyrosine phosphatase receptor F (PTPRF), a downstream target of PPARγ, was markedly induced in FE1.2-PPARγhi cells. A PPARγ consensus binding site (AGGTCA) was identified in the ptprf promoter, and an electrophoretic mobility shift assay confirmed that PPARγ bind to this promoter. Similar to the effect of vector-mediated overexpression of PPARγ, ectopic overexpression of PTPRF in FE1.2 cells led to reduced proliferation. Furthermore, a PPARγ antagonist (GW9662) and PTP inhibitor (NSC87877) abrogated the suppressive function of PPARγ and PTPRF in FE1.2 cells, respectively. PPARγ overexpression or activation suppressed the progression and distant organ metastasis of breast cancer cells in a NOD/SCID mouse model.These results suggest that PPARγ inhibits tumor cell proliferation, at least in part, through direct regulation of the ptprf gene and that PPARγ is a potential target for breast cancer treatment.Keywords:
Rosiglitazone
Peroxisome proliferator-activated receptor gamma (PPARγ) activation decreased serum testosterone (T) in women with hyperthecosis and/or polycystic ovary syndrome and reduced the conversion of androgens to estradiol (E2) in female rats. This implies modulation of female sex steroid hormones by PPARγ. It is not clear if PPARγ modulates sex steroid hormones in diabetic males. Because PPARγ activation by thiazolidinedione increased insulin sensitivity in type 2 diabetes, understanding the long term impact of PPARγ activation on steroid sex hormones in males is critical. Our objective was to determine the effect of PPARγ activation on serum and intratesticular T, luteinizing hormone (LH), follicle stimulating hormone (FSH) and E2 concentrations in male Zucker diabetic fatty (ZDF) rats treated with the PPARγ agonist rosiglitazone (a thiazolidinedione). Treatment for eight weeks increased PPARγ mRNA and protein in the testis and elevated serum adiponectin, an adipokine marker for PPARγ activation. PPARγ activation did not alter serum or intratesticular T concentrations. In contrast, serum T level but not intratesticular T was reduced by diabetes. Neither diabetes nor PPARγ activation altered serum E2 or gonadotropins FSH and LH concentrations. The results suggest that activation of PPARγ by rosiglitazone has no negative impact on sex hormones in male ZDF rats.
Rosiglitazone
Thiazolidinedione
Sex steroid
Cite
Citations (15)
We examined the effects of activation of peroxisome proliferator–activated receptor (PPAR)α, PPARγ, and both of them in combination in obese diabetic KKAy mice and investigated the mechanisms by which they improve insulin sensitivity. PPARα activation by its agonist, Wy-14,643, as well as PPARγ activation by its agonist, rosiglitazone, markedly improved insulin sensitivity. Interestingly, dual activation of PPARα and -γ by a combination of Wy-14,643 and rosiglitazone showed increased efficacy. Adipocyte size in Wy-14,643–treated KKAy mice was much smaller than that of vehicle- or rosiglitazone-treated mice, suggesting that activation of PPARα prevents adipocyte hypertrophy. Moreover, Wy-14,643 treatment reduced inflammation and the expression of macrophage-specific genes in white adipose tissue (WAT). Importantly, Wy-14,643 treatment upregulated expression of the adiponectin receptor (AdipoR)-1 and AdipoR2 in WAT, which was decreased in WAT of KKAy mice compared with that in nondiabetic control mice. Furthermore, Wy-14,643 directly increased expression of AdipoRs and decreased monocyte chemoattractant protein-1 expression in adipocytes and macrophages. Rosiglitazone increased serum adiponectin concentrations and the ratio of high molecular weight multimers of adiponectin to total adiponectin. A combination of rosiglitazone and Wy-14,643 increased both serum adiponectin concentrations and AdipoR expression in WAT. These data suggest that PPARα activation prevents inflammation in WAT and that dual activation of PPARα and -γ enhances the action of adiponectin by increasing both adiponectin and AdipoRs, which can result in the amelioration of obesity-induced insulin resistance.
Peroxisome proliferator
Cite
Citations (398)
Lipid accumulation in nonadipose tissues is closely related to the development of type 2 diabetes in obese subjects. We examined the potential preventive effect of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ stimulation on the development of diabetes in obese diabetes-prone OLETF rats. Chronic administration of a PPAR-α agonist (0.5% [wt/wt] fenofibrate) or a PPAR-γ agonist (3 mg · kg−1 · day−1 rosiglitazone) completely prevented the development of glycosuria. Pancreatic islets from untreated OLETF rats underwent sequential hypertrophy and atrophy, which was completely prevented by chronic fenofibrate treatment. In contrast, rosiglitazone treatment did not affect islet hypertrophy at earlier stages but prevented β-cell atrophy at later stages. Fenofibrate treatment decreased body weight and visceral fat, whereas rosiglitazone treatment increased body weight. Despite the opposite effects on adiposity, both drugs were equally effective in improving insulin actions in skeletal muscle. Furthermore, both drugs significantly decreased the triglyceride content in the soleus muscle and pancreatic islets. The present study demonstrates that the PPAR-α agonist fenofibrate prevents the development of diabetes in OLETF rats by reducing adiposity, improving peripheral insulin action, and exerting beneficial effects on pancreatic β-cells.
Fenofibrate
Rosiglitazone
Pancreatic Islets
Cite
Citations (150)
Peroxisome proliferator-activated receptor (PPAR)γ, a transcription factor belonging to the nuclear receptor superfamily, is essential for adipogenesis. PPARγ is recognized as a major target for the insulin-sensitizing effects of the thiazolidinediones. Previous studies have demonstrated that heterozygous PPARγ-deficient mice are protected from high-fat diet (HFD)-induced adipocyte hypertrophy, obesity and insulin resistance, which suggests that PPARγ may have a pivotal role in adipocyte hypertrophy, obesity and insulin resistance. In this study, we generated transgenic mice with the gain-of-function PPARγ Ser112Ala mutation (S112A mice) using the aP2 promoter, to elucidate the impact of increased PPARγ activity in mature adipocytes. Despite a 2-3-fold increase in the adipocyte PPARγ2 gene expression and PPARγ activity, the S112A mice showed comparable adiposity and insulin sensitivity to wild-type mice under both normal and HFD conditions. Although the expression levels of the PPARγ target genes involved in lipid metabolism, such as aP2 and stearoyl-CoA desaturase 1, were upregulated in the white adipose tissue of the S112A mice, the serum levels of free fatty acid, triglyceride, adiponectin and leptin, as well as the oxygen consumption, were comparable between the wild-type and S112A mice under the HFD condition. Moreover, treatment with rosiglitazone ameliorated insulin resistance and glucose intolerance to a similar degree in the two genotypes under the HFD condition. In conclusion, whereas the 50% decrease in PPAR γ activity showed protection from HFD-induced obesity and insulin resistance, in the present study, the 2-3-fold increase in PPARγ2 expression and PPARγ activity failed to show obesity and insulin resistance even under the HFD condition.
Rosiglitazone
Cite
Citations (28)
Peroxisome proliferator-activated receptor (PPAR)-γ agonists are insulin sensitizers, whereas PPARα agonists are lipid-lowering agents in humans. Chronic treatment with PPARγ agonists has been shown to prevent the onset of diabetes in young Zucker diabetic fatty (ZDF) rats; however, the effects of PPARα agonists have not been well characterized in this model. Here we investigated chronic efficacy of PPARα and nonthiazolidinedione (nTZD) PPARγ agonists on the onset of diabetes in 6-wk-old male ZDF rats. Whereas treatment with the nTZD PPARγ agonist completely prevented development of hyperglycemia, PPARα activation was associated with lowering of food intake and body weight and reductions in fed and fasting hyperglycemia, with prevention of the hyperinsulinemic peak preceding the development of hyperglycemia in ZDF rats. Both compounds improved glucose tolerance during an oral glucose tolerance test with concomitant increases in insulin response. Such improvements of insulin secretion were associated with increased islet to total pancreatic area ratio and pancreatic insulin contents. Hyperinsulinemic-euglycemic clamp studies demonstrated that nTZD PPARγ reduced basal endogenous glucose production and increased insulin-stimulated glucose disposal, consistent with an improved insulin action as a cause of the improved glucose homeostasis. In contrast, activation of PPARα did not significantly improve glucose metabolism during the hyperinsulinemic-euglycemic clamp. In conclusion, chronic treatment of ZDF rats with a PPARγ agonist completely prevented the onset of diabetes by improving both insulin action and secretion, whereas PPARα agonism was partially effective, primarily by improving the pancreatic islet insulin response. Unlike the PPARγ agonist, the PPARα agonist demonstrated efficacy without inducing body weight gain and cardiomegaly. This study suggests a possible role for PPARα agonists in the prevention of type 2 diabetes mellitus.
Rosiglitazone
PPAR agonist
Cite
Citations (42)
Peroxisome proliferator-activated receptor-γ (PPARγ) activation up-regulates thermogenesis-related genes in rodent white and brown adipose tissues (WAT and BAT) without increasing whole-body energy expenditure. We tested here whether such dissociation is the result of a negative modulation of sympathetic activity to WAT and BAT and thyroid axis components by PPARγ activation. Administration of the PPARγ agonist rosiglitazone (15 mg/kg·d) for 7 d to male Sprague Dawley rats increased food intake (10%), feed efficiency (31%), weight gain (45%), spontaneous motor activity (60%), and BAT and WAT mass and reduced whole-body oxygen consumption. Consistent with an anabolic setting, rosiglitazone markedly reduced sympathetic activity to BAT and WAT (>50%) and thyroid status as evidenced by reduced levels of plasma thyroid hormones (T4 and T3) and mRNA levels of BAT and liver T3-generating enzymes iodothyronine type 2 (−40%) and type 1 (−32%) deiodinases, respectively. Rosiglitazone also decreased mRNA levels of the thyroid hormone receptor (THR) isoforms α1 (−34%) and β (−66%) in BAT and isoforms α1 (−20%) and α2 (−47%) in retroperitoneal WAT. These metabolic effects were associated with a reduction in mRNA levels of the pro-energy expenditure peptides CRH and CART in specific hypothalamic nuclei. A direct central action of rosiglitazone is, however, unlikely based on its low brain uptake and lack of metabolic effects of intracerebroventricular administration. In conclusion, a reduction in BAT sympathetic activity and thyroid status appears to, at least partly, explain the PPARγ-induced reduction in energy expenditure and the fact that up-regulation of thermogenic gene expression does not translate into functional stimulation of whole-body thermogenesis in vivo.
Rosiglitazone
Thermogenin
Thyroid hormone receptor
Iodothyronine deiodinase
Cite
Citations (110)
Rosiglitazone
Fenofibrate
Cite
Citations (66)
Rosiglitazone
Fenofibrate
Cite
Citations (149)
Pioglitazone
Rosiglitazone
Thiazolidinedione
Hyperinsulinemia
Diabetic Cardiomyopathy
GLUT4
Cite
Citations (22)
FK506-binding protein-51 (FKBP51) is a molecular cochaperone recently shown to be a positive regulator of peroxisome proliferator-activated receptor (PPAR)γ, the master regulator of adipocyte differentiation and function. In cellular models of adipogenesis, loss of FKBP51 not only reduced PPARγ activity but also reduced lipid accumulation, suggesting that FKBP51 knock-out (KO) mice might have insufficient development of adipose tissue and lipid storage ability. This model was tested by examining wild-type (WT) and FKBP51-KO mice under regular and high-fat diet conditions. Under both diets, FKBP51-KO mice were resistant to weight gain, hepatic steatosis, and had greatly reduced white adipose tissue (WAT) but higher amounts of brown adipose tissue. Under high-fat diet, KO mice were highly resistant to adiposity and exhibited reduced plasma lipids and elevated glucose and insulin tolerance. Profiling of perigonadal and sc WAT revealed elevated expression of brown adipose tissue lineage genes in KO mice that correlated increased energy expenditure and a shift of substrate oxidation to carbohydrates, as measured by indirect calorimetry. To directly test PPARγ involvement, WT and KO mice were fed rosiglitazone agonist. In WT mice, rosiglitazone induced whole-body weight gain, increased WAT mass, a shift of substrate oxidation to lipids, and elevated expression of PPARγ-regulated lipogenic genes in WAT. In contrast, KO mice had reduced rosiglitazone responses for these parameters. Our results identify FKBP51 as an important regulator of PPARγ in WAT and as a potential new target in the treatment of obesity and diabetes.
Rosiglitazone
Steatosis
Cite
Citations (73)