Skp2 is frequent amplified and overexpressed in breast cancer, making it a potential molecular target for cancer therapy. The objective of this study was to examine the effect of PPARγ overexpression on Skp2 expression in breast cancer cell lines. First, we investigated the role of PPARγ and Skp2 in human breast cancer progression. Immunohistochemical analysis of 70 specimens on formalin-fixed paraffin sections was performed. Furthermore in vitro, Western blot analysis was used to study the relationship between PPARγ and Skp2. We found that the expression of PPARγ and Skp2 expression was inverse correlation whether in vivo or in vitro. In addition, PPARγ overexpression can down-regulate the expression of Skp2 mRNA and protein in breast cancer cells. PPARγ overexpression decreased breast cancer cell proliferation and induced spontaneous apoptosis even in the absence of exogenous ligand. These PPARγ-overexpressing cells were dramatically more sensitive to PPARγ ligand-induced apoptosis compared with parental or Myc-control transfected cells. Overexpressing of Skp2 partially reversed PPARγ's pro-apoptotic and anti-proliferative abilities. These results suggested that PPARγ's pro-apoptotic and anti-proliferative abilities appear to be triggered at least in part by the modulation of Skp2.
Src-suppressed C kinase substrate (SSeCKS) is involved in inflammation in the central nervous system (CNS), and plays a role in control of cell signaling and cytoskeletal arrangement. However, the expression and function of SSeCKS and its function in multiple sclerosis (MS) and its common animal model, experimental autoimmune encephalomyelitis (EAE) remained to be elucidated. In the present study, we first reported that SSeCKS was remarkably increased in astrocytes of EAE rats in vivo. TNF-alpha and NO were significantly induced in astrocytes stimulated with LPS/IFN-gamma in vitro, which was blocked in astrocytes transfected with SSeCKS siRNA. These results indicated that SSeCKS played a role in the production of TNF-alpha and NO in astrocytes with inflammatory stimulation. As excessive release of TNF-alpha and NO were major mediators in autoimmune diseases and correlated with oligodendrocyte cell death, we further investigated whether SSeCKS participated in oligodendrocyte apoptosis. Conditioned media (CM) from astrocytes treated with LPS/IFN-gamma decreased oligodendrocyte cell viability, while siRNA targeted to SSeCKS in astrocytes inhibited oligodendrocyte cell death. The results from antibody neutralization and NO inhibition suggested that the oligodendrocyte apoptosis may be due to the production of astrocyte-derived proinflammatory factors (TNF-alpha and NO). These findings revealed that there was a pathogenic interaction between SSeCKS expression in astrocytes and oligodendrocyte apoptosis. Understanding the mechanism of SSeCKS in the pathogenesis of EAE may contribute to the development of new therapeutic strategies against EAE and MS.
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