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

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...

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Bibliographic Details
Published in:Molecular carcinogenesis 2013-01, Vol.52 (1), p.1
Main Authors: Zurlo, Diana, Leone, Cinzia, Assante, Gemma, Salzano, Salvatore, Renzone, Giovanni, Scaloni, Andrea, Foresta, Caterina, Colantuoni, Vittorio, Lupo, Angelo
Format: Article
Language:English
Subjects:
Antineoplastic Agents - pharmacology
Cell Proliferation - drug effects
Cell Survival - drug effects
Colonic Neoplasms - metabolism
Cyclin-Dependent Kinase 2 - metabolism
Cyclin-Dependent Kinase Inhibitor p21 - biosynthesis
Cyclin-Dependent Kinase Inhibitor p21 - genetics
Cyclins - metabolism
Gene Expression Regulation, Neoplastic - drug effects
HT29 Cells
Humans
MAP Kinase Signaling System
Mutation
Naphthalenes - pharmacology
Promoter Regions, Genetic
Sp1 Transcription Factor - metabolism
Tumor Suppressor Protein p53 - metabolism
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Summary: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 fluorescence activated cell sorting analysis on synchronized HT-29  cells, and was associated with an early and robust over-expression of p21(waf1/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 p21(waf1/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 signaling pathways both involved in the inhibition of cell proliferation. Finally, we showed that the increase of p21(waf1/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 p21(waf1/cip1) expression.
ISSN:1098-2744
DOI:10.1002/mc.20872