Cladosporols, purified and characterized as secondary metabolites from Cladosporium tenuissimum, display an antifungal activity. In this study, we tested the antiproliferative properties of cladosporol A, the main isoform of this metabolite family, against human cancer cell lines. By assessing cell viability, we found that cladosporol A inhibits the growth of various human colon cancers derived cell lines (HT-29, SW480 and CaCo-2) in a time- and concentration-dependent manner, specifically of HT-29 cells. The reduced cell proliferation was due to a G1-phase arrest, as assessed by FACS analysis on synchronized HT-29 cells, and was associated with an early and robust overexpression of p21waf1/cip1, the well-known cyclin-dependent kinases inhibitor. This suggests that the drug may play a role in the control of cancer cell proliferation. Consistently, cyclin D1, cyclin E, CDK2 and CDK4 proteins were reduced and histone H1-associated CDK2 kinase activity inhibited. In addition to p21waf1/cip1, exposure to 20 μM cladosporol A caused a simultaneous increase of pERK and pJNK, suggesting that this drug activates a circuit that integrates cell cycle regulation and the signalling pathways both involved in the inhibition of cell proliferation. Finally, we showed that the increase of p21waf1/cip1 expression was generated by a Sp1–dependent p53-independent stimulation of its gene transcription as mutagenesis of the Sp1 binding sites located in the p21 proximal promoter abolished induction. To our knowledge, this is the first report showing that cladosporol A inhibits colon cancer cell proliferation by modulating p21waf1/cip1 expression.
|Titolo:||Cladosporol A stimulates G1-phase arrest of the cell cycle by up-regulation of p21 (waf1/cip1) expression in human colon carcinoma HT-29 cells|
|Data di pubblicazione:||2013|
|Appare nelle tipologie:||1.1 Articolo in rivista|
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|Cladosporol a stimulates G1phase arrest of the cell cycle by upregulation of p21waf1_cip1 expression in human colon carcinoma HT29 cells.pdf||N/A||Non specificato||Administrator Richiedi una copia|