Acetaldehyde activates Jun/AP-1 expression and DNA binding activity in human oral keratinocytes.
Oral cancer is a significant health problem, particularly among individuals that ingest alcohol in combination with the use of tobacco products. The enhanced development of tobacco-initiated oral cancers by ethanol suggests that ethanol or one of its metabolites may act as a type of tumor promoter. Nevertheless, the mechanisms underlying the ability of ethanol to enhance oral carcinogenesis remain unclear. We hypothesize that acetaldehyde, the first metabolite of ethanol, may activate the expression and/or activity of Jun/AP-1 in oral keratinocytes analogous to the phorbol ester TPA and other tumor promoters in epidermal keratinocytes. To test this hypothesis, we treated HPV immortalized, non-tumorigenic human oral keratinocytes with acetaldehyde at various concentrations and for various times and measured several parameters of Jun/AP-1expression and function. Our results indicated that c-Jun mRNA and protein levels increased in the acetaldehyde treated cells compared to untreated control cells. Moreover, Jun/AP-1 DNA binding activity was rapidly activated by acetaldehyde in a dose-dependent fashion. The increases in Jun protein and AP-1 DNA binding activity were accompanied by increased transactivation of an AP-1 responsive reporter construct as well as increased transcript levels of a candidate AP-1 responsive gene, stromelysin 3. The levels of acetaldehyde employed were minimally toxic to the cells as determined by MTT assays. Thus, acetaldehyde was found to activate the expression and activity of an oncogenic transcription factor in HPV-initiated cells. Taken together, these results suggest that acetaldehyde may participate, at least in part, in the promotion stage of oral carcinogenesis.
Timmons
Sherry R
SR
Oral Sciences Graduate Program, B180ML, The University of Iowa, Iowa City, IA 52242, USA.
Nwankwo
Joseph O
JO
Domann
Frederick E
FE
D000079:Acetaldehyde / Q000009:adverse effects*; D015153:Blotting, Western; D002461:Cell Line, Transformed; D004247:DNA / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D024202:Electrophoretic Mobility Shift Assay; D015870:Gene Expression; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism; D053507:Matrix Metalloproteinase 11; D008666:Metalloendopeptidases / Q000235:genetics; D027383:Papillomaviridae; D011485:Protein Binding; D016755:Proto-Oncogene Proteins c-jun / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D018808:Transcription Factor AP-1 / Q000187:drug effects* / Q000378:metabolism
D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D004247:DNA; D053507:Matrix Metalloproteinase 11; D008666:Metalloendopeptidases; D000079:Acetaldehyde