Curcumin upregulates insulin-like growth factor binding protein-5 (IGFBP-5) and C/EBPα during oral cancer suppression

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 alpha (C/EBP alpha) 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/EBP alpha-binding element that is indispensable for curcumin-mediated IGFBP-5 upregulation. Chromatin immunoprecipitation assays revealed that in vivo binding of C/EBP alpha to this region was remarkably increased in the presence of curcumin. Curcumin increased nuclear C/EBP alpha expression and IGFBP-5 expression through p38 activation and this was abrogated by 5B203580 treatment. Furthermore, MKK6 expression activated p38 and C/EBP alpha, 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/EBP alpha transactivator by interacting with binding elements in the IGFBP-5 promoter. The consequential upregutation of C/EBP alpha and IGFBP-5 by curcumin is crucial to the suppression of oral carcinogenesis.