Abstract
Curcumin is a common food ingredient derived from the plant Curcuma longa and is a potent drug against tumorigenesis. Both insulin‐like growth factor binding protein‐5 (IGFBP‐5) and CCAAT/enhancer‐binding protein α (C/EBPα) are suppressors of head and neck carcinogenesis. We identified curcumin as an inducer of IGFBP‐5 expression in multiple types of oral keratinocytes; furthermore, curcumin induces IGFBP‐5 promoter activity in SAS oral cancer cells. Promoter deletion mapping identified a region (nt −71 to nt −59 relative to the transcription start site) as containing a C/EBPα‐binding element that is indispensable for curcumin‐mediated IGFBP‐5 upregulation. Chromatin immunoprecipitation assays revealed that in vivo binding of C/EBPα to this region was remarkably increased in the presence of curcumin. Curcumin increased nuclear C/EBPα expression and IGFBP‐5 expression through p38 activation and this was abrogated by SB203580 treatment. Furthermore, MKK6 expression activated p38 and C/EBPα, increasing IGFBP‐5 promoter activity and expression. Finally, curcumin‐induced IGFBP‐5 expression is associated with the suppression of xenograft tumorigenesis in mice due to oral cancer cells. We conclude that curcumin activates p38, which, in turn, activates the C/EBPα transactivator by interacting with binding elements in the IGFBP‐5 promoter. The consequential upregulation of C/EBPα and IGFBP‐5 by curcumin is crucial to the suppression of oral carcinogenesis.