To better define the effect of endogenous transactivation of PPARγ in liver carcinogenesis, we examined its functional consequences by overexpression in the human HCC cell line Hep3B. The choice of human HCC Hep3B cells for this study was based on two observations: (1) higher transfection efficiency learn more of Ad-PPARγ and Ad-LacZ in Hep3B compared with other HCC cell lines (e.g., HepG2), and (2) previous demonstration of rosiglitazone’s efficacy in inhibiting tumor cell growth in this
cell line.7 In this study, increased PPARγ expression led to the inhibition of cell growth in a time-dependent and dose-dependent manner. In the presence of the PPARγ agonist rosiglitazone, a more pronounced diminution in Hep3B cell viability was observed, lending further support to its role in inhibiting HCC development. To further investigate the mechanism by which PPARγ regulates cell growth, we performed FACS; cell cycle distribution analysis revealed significantly more Ad-PPARγ cells were arrested in the G2/M phase, with a concomitant reduction in cellular proliferation compared with Ad-LacZ controls. To explore the molecular mechanism underlying G2/M phase
arrest, we studied the regulatory proteins that controlled the G2/M checkpoint Small molecule library cell assay in the cell cycle. G2/M phase arrest by PPARγ was associated with Cdc25C phosphatase activation by Ser216 phosphorylation. After phosphorylation, Cdc25C
is known to bind to members of the 14-3-3 proteins, sequestering it into the cytoplasm, thereby preventing premature mitosis.27 Cdc25C also plays a critical role in the dephosphorylation of Cdc2 on Tyr15; 上海皓元医药股份有限公司 Cdc2 is a major kinase involved in G2/M cell cycle control and the entry of all eukaryotic cells into mitosis,28 and inhibiting Cdc25C activity may result in the Tyr15 phosphorylation and inactivation of Cdc2. Cell cycle arrest caused by the overexpression of p53 has been associated with induction of p21 and p27.29 Troglitazone was associated with induction of p27, but not p21 in Hep3B cells.7 The reason for the inability of enhanced PPARγ to induce p21 and p27 in Hep3B cells could be explained by p53 deletion in this cell line. The mechanism of troglitazone-mediated p27 induction is likely to be independent of PPARγ. A disruption in the balance between cellular proliferation and apoptosis may contribute to the initiation and progression of cancer.30 In contrast, resistance of apoptosis is a likely requirement for cancer cell maintenance.
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