FH535 potentiation of cigarette smoke condensate cytotoxicity is associated with changes in β-catenin and EGR-1 signaling.
Cigarette smoke condensate (CSC) has been reported to elicit morphological and transcriptional changes that suggest epithelial-to-mesenchymal transition (EMT) in cultured bronchial epithelial cells. The transdifferentiation potential of acute and prolonged CSC exposure alone or in combination with the β-catenin inhibitor, FH535, was investigated in the bronchial epithelial cell line, BEAS-2B, through assessment of cell morphology, transcript expression, protein expression, and protein localization. Changes in morphology, β-catenin translocation, E-cadherin expression, metalloproteinase expression, and fibronectin could be demonstrated independent of molecular or physiological evidence of EMT. FH535 was shown to increase CSC-induced cytotoxicity and depress β-catenin expression. However, FH535 effects were not limited to the β-catenin pathway as it also blocked the expression of early growth responsive protein 1 (EGR-1) target genes, fibronectin and phosphatase and tensin homologue, without affecting EGR-1 nuclear accumulation.
A.W. Spears Research Center, Lorillard Tobacco Company, Greensboro, NC 27420, USA. tox.bill@gmail.com
William W
WW
Polk
D001980:Bronchi / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement; D054338:Cell Transdifferentiation / Q000187:drug effects; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D012906:Smoke / Q000009:adverse effects*; D013449:Sulfonamides / Q000633:toxicity*; D000070876:Tensins; D014026:Nicotiana / Q000009:adverse effects*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
C495270:CTNNB1 protein, human; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; C575430:FH535; D005353:Fibronectins; D008840:Microfilament Proteins; D012906:Smoke; D013449:Sulfonamides; D000070876:Tensins; D051176:beta Catenin; D010744:Phosphoric Monoester Hydrolases