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 a (C/EBPa) 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 271 to nt 259 relative to the transcription start site) as containing a C/EBPa-binding element that is indispensable for curcuminmediated IGFBP-5 upregulation. Chromatin immunoprecipitation assays revealed that in vivo binding of C/EBPa to this region was remarkably increased in the presence of curcumin. Curcumin increased nuclear C/EBPa expression and IGFBP-5 expression through p38 activation and this was abrogated by SB203580 treatment. Furthermore, MKK6 expression activated p38 and C/EBPa, 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/EBPa transactivator by interacting with binding elements in the IGFBP-5 promoter. The consequential upregulation of C/EBPa and IGFBP-5 by curcumin is crucial to the suppression of oral carcinogenesis.Insulin-like growth factors (IGFs) that bind IGF receptors (IGFRs) with high affinity play important roles in regulating cell phenotypes, including proliferation, differentiation, migration and apoptosis. Diferuloylmethane (Curcumin), found in significant amounts in the Indian spice turmeric, is a polyphenol derived from the plant Curcuma longa and is a common food ingredient across the world. 8,9 Accumulated evidence has indicated that this polyphenol can be used to both prevent and treat cancer. 10,11 Curcumin exhibits cancer chemopreventive effects in a range of animal models of chemical carcinogenesis, including those resulting in head and neck squamous cell carcinoma (HNSCC) and OSCC. 12,13 This compound also has anti-oxidative effects, anti-inflammatory effects, anti-

Expression of IGFBP-5 in GEC is associated with anti-apoptosis, migration and differentiation of GEC. These phenotypic effects may be associated with focal adhesion kinase and are advantageous for re-epithelization of GEC and the maintenance of gingival health.