title: Cladosporol A, a new peroxisome proliferator-activated receptor γ (PPARγ) ligand, inhibits colorectal cancer cells proliferation through β-catenin/TCF pathway inactivation.
abstract: BACKGROUND
  Cladosporol A, a secondary metabolite from Cladosporium tenuissimum, exhibits antiproliferative properties in human colorectal cancer cells by modulating the expression of some cell cycle genes (p21(waf1/cip1), cyclin D1).
  
  
  METHODS
  PPARγ activation by cladosporol A was studied by overexpression and RNA interference assays. The interactions between PPARγ and Sp1 were investigated by co-immunoprecipitation and ChIp assays. β-Catenin subcellular distribution and β-catenin/TCF pathway inactivation were analyzed by western blot and RTqPCR, respectively. Cladosporol A-induced β-catenin proteasomal degradation was examined in the presence of the specific inhibitor MG132.
  
  
  RESULTS
  Cladosporol A inhibits cell growth through upregulation of p21(waf1/cip1) gene expression mediated by Sp1-PPARγ interaction. Exposure of HT-29 cells to cladosporol A causes β-catenin nuclear export, proteasome degradation and reduced expression of its target genes. Upon treatment, PPARγ also activates E-cadherin gene at the mRNA and protein levels.
  
  
  CONCLUSIONS
  In this work we provide evidence that PPARγ mediates the anti-proliferative action of cladosporol A in colorectal cancer cells. Upon ligand activation, PPARγ interacts with Sp1 and stimulates p21(waf1/cip1) gene transcription. PPARγ activation causes degradation of β-catenin and inactivation of the downstream target pathway and, in addition, upregulates E-cadherin expression reinforcing cell-cell interactions and a differentiated phenotype.
  
  
  CONCLUSIONS
  We elucidated the molecular mechanisms by which PPARγ mediates the anticancer activity of cladosporol A.
authors.affiliation: Dipartimento di Scienze e Tecnologie, Università del Sannio, via Port'Arsa 11, 82100 Benevento, Italy.
authors.forename: Diana
authors.initials: D
authors.lastname: Zurlo
authors.affiliation: Dipartimento di Patologia Vegetale, Università degli Studi di Milano, via Celoria, 2, 20133 Milano, Italy.
authors.forename: Gemma
authors.initials: G
authors.lastname: Assante
authors.affiliation: Dipartimento di Scienze delle Produzioni Agroalimentari e dell'Ambiente (DiSPAA), Università degli Studi di Firenze, Piazzale delle Cascine, 2850144 Firenze, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Moricca
authors.affiliation: Dipartimento di Scienze e Tecnologie, Università del Sannio, via Port'Arsa 11, 82100 Benevento, Italy.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Colantuoni
authors.affiliation: Dipartimento di Scienze e Tecnologie, Università del Sannio, via Port'Arsa 11, 82100 Benevento, Italy. Electronic address: lupo@unisannio.it.
authors.forename: Angelo
authors.initials: A
authors.lastname: Lupo
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D019073:HT29 Cells; D006801:Humans; D008024:Ligands; D009281:Naphthalenes / Q000378:metabolism* / Q000494:pharmacology; D047495:PPAR gamma / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D016329:Sp1 Transcription Factor / Q000378:metabolism; D051820:TCF Transcription Factors / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D008024:Ligands; D009281:Naphthalenes; D047495:PPAR gamma; D016329:Sp1 Transcription Factor; D051820:TCF Transcription Factors; D051176:beta Catenin; C548360:cladosporol
keywords: Cell proliferation; Cladosporol A; E-cadherin; Transcription; p21(waf1/cip1); β-catenin