title: The mycotoxin patulin decreases expression of density-enhanced phosphatase-1 by down-regulating PPARγ in human colon cancer cells.
abstract: Patulin is a mycotoxin that is found mainly in apple products and causes symptoms such as bleeding from the digestive tract and diarrhea. Efforts to elucidate the mechanism of its toxicity have focused on protein tyrosine phosphatases (PTPs), which regulate the function of tight junctions (TJs) in colon epithelial cells. Patulin reacts with the conserved cysteine residues in the catalytic domains of PTP isoforms. Treatment of Caco-2 human colon cancer cells, used as a colon epithelial model, with 50 µM patulin decreased the level of density-enhanced phosphatase-1 (DEP-1) protein to 30% of the control level after 6 h. The level of DEP-1 mRNA was also decreased during 24 h after treatment with patulin. Moreover, knockdown of DEP-1 increased the level of phosphorylated claudin-4. Destruction of TJs by patulin treatment was observed by immunostaining with an antibody against zonula occludens (ZO)-1. To better understand the mechanistic basis of the decrease in DEP-1 mRNA levels, we searched for a cis-element upstream of the DEP-1 gene and found an element responsive to the peroxisome proliferator-activated receptor gamma (PPARγ) protein. Using a PPARγ-specific antibody, we showed a decrease in PPARγ abundance to 42% of the control level within 6 h after treatment with patulin. PPARγ has four cysteine residues that are involved in zinc finger formation. Our data suggest that DEP-1 affects TJ function and that PPARγ might control DEP-1 expression. Therefore, the toxicity of patulin to cellular functions might be attributable to its ability to down-regulate the expression of DEP-1 and PPARγ.
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Agriculture and Life Science, Hirosaki University.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Katsuyama
authors.forename: Tomomi
authors.initials: T
authors.lastname: Konno
authors.forename: Shuji
authors.initials: S
authors.lastname: Shimoyama
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kikuchi
mesh_terms: D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000235:genetics*; D015536:Down-Regulation / Q000187:drug effects*; D004848:Epithelium / Q000187:drug effects / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D008954:Models, Biological; D047495:PPAR gamma / Q000378:metabolism*; D010365:Patulin / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3 / Q000235:genetics / Q000378:metabolism; D062725:Tight Junction Proteins / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D047495:PPAR gamma; D062725:Tight Junction Proteins; D010365:Patulin; C486288:PTPRJ protein, human; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3