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Abstract: ETS1, which belongs to the ETS transcription factor family, plays important roles in diverse aspects of cancer such as drug resistance and metastasis. In the present study, we examined the functional roles of ETS1 in paclitaxel resistance and invasion using human prostate cancer PC3cells and paclitaxel-resistant PC3PR cells established from PC3 cells. Our results showed that ETS1mRNA and protein expression was markedly up-regulated in paclitaxel-resistant PC3PR cells compared with paclitaxel-sensitive PC3 cells. The mRNA levels of MDR1 as well as MMP1, MMP3, MMP9 and uPA were positively correlated with that of ETS1. In PC3PR cells, silencing of ETS1 expression by siRNAs inhibited the activity of the MDR1 promoter containing ETS binding sites, reduced the mRNA and protein levels of MDR1 and suppressed paclitaxel resistance. Furthermore, ETS1 knockdown decreased secretion of MMP9 as well as its intracellular mRNA level, and dramatically inhibited invasion of PC3PR cells. Our results suggest that ETS1 promotes paclitaxel resistance and invasion in part by up-regulating MDR1 and MMP9 expression. Taken together, a novel therapeutic strategy targeting the ETS1 gene could be designed to overcome chemoresistance and metastasis of taxane-resistant, hormone-refractory prostate cancer. [Copyright &y& Elsevier]

Perivascular adipose tissue (PAT) is associated with vascular homeostasis; however, its causal effect on atherosclerosis currently remains undefined. Here, we investigated the effect of experimental PAT transplantation on atherosclerosis. The thoracic periaortic adipose tissue (tPAT) was dissected from 16-week-old wild-type mice and transplanted over the infrarenal aorta of 20-week-old apoE deficient ( apoE −/− ) mice fed high-cholesterol diet for 3 months. Oil-red O staining after 4 weeks showed a significant 20% decrease in the atherosclerotic lesion of suprarenal aorta compared with that of sham control mice, while that of infrarenal aorta showed no difference between the two groups. TGF-β1 mRNA expression was significantly higher in grafted tPAT than donor tPAT, accompanied by a significant increase in serum TGF-β1 concentration, which was inversely correlated with the suprarenal lesion area (r = −0.63, P  = 0.012). Treatment with neutralizing TGF-β antibody abrogated the anti-atherogenic effect of tPAT transplantation. Immunofluorescent analysis of grafted tPAT showed that TGF-β-positive cells were co-localized with Mac-2-positive cells and this number was significantly increased compared with donor tPAT. There was also marked increase in mRNA expression of alternatively activated macrophages-related genes. Furthermore, the percentage of eosinophils in stromal vascular fraction of donor tPAT was much higher than that in epididymal white adipose tissue, concomitant with the significantly higher protein level of IL-4. IL-4 mRNA expression levels in grafted tPAT were increased in a time-dependent manner after tPAT transplantation. Our findings show that tPAT transplantation inhibits atherosclerosis development by exerting TGF-β1-mediated anti-inflammatory response, which may involve alternatively activated macrophages. [ABSTRACT FROM AUTHOR]

Brown adipose tissue (BAT) has been found as an endocrine organ that maintains metabolic homeostasis; however, the effects on atherosclerosis remain undefined. Here, we investigated the effect of experimental BAT transplantation on atherosclerosis. Interscapular BAT was dissected from wild-type mice and transplanted into the visceral cavity of 12-week-old apoE −/− mice. Oil-red O staining of whole aortas after 3 months of a high-cholesterol diet showed a significant decrease in atherosclerotic lesion area in BAT-transplanted mice by 32% compared with the sham control mice. Lipid profiles, except for serum triglyceride level, showed no difference between the 2 groups. BAT-transplanted mice showed higher concentrations of serum noradrenalin, fibroblast growth factor 21 (FGF-21), and adiponectin. Treatment with the β3-adrenergic receptor (AR) blocker completely abrogated the atheroprotective effects of BAT transplantation, with serum concentrations of FGF-21 and adiponectin being equivalent between the 2 groups. Homologous transplantation of BAT from apoE −/− mice also showed a significant decrease in atherosclerotic lesion area by 28% without affecting lipid profiles, while epidydimal white adipose tissue transplantation did not affect atherosclerosis. Serum and endogenous BAT concentrations of FGF-21 were significantly higher in BAT-transplanted mice than sham control mice. Concomitantly, serum adiponectin levels were elevated in BAT-transplanted mice and showed a significant inverse correlation with atherosclerotic lesion area. Our findings show for the first time that atheroprotective effect of BAT transplantation is BAT-specific and independent of lipid-lowering effect, accompanied by AR-mediated activation of the FGF-21-adiponectin axis. [ABSTRACT FROM AUTHOR]