Curcumin induces insulin-like growth factor binding protein-5 (IGFBP-5) expression through up-regulating CCAAT/Enhancer-binding protein-α (C/EBPα) in oral keratinocytes

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Curcumin is a common food ingredient derived from the plant Curcuma longa, which is a potent drug against neoplastic cells. Both insulin-like growth factor binding protein-5 (IGFBP-5) and CCAAT/enhancer-binding protein α (C/EBPα) are suppressors for head and neck carcinogenesis. In the present study, we identified that curcumin induced IGFBP-5 expression in multiple oral keratinocytes. Curcumin also induced IGFBP-5 promoter activity in SAS oral cancer cells. Knockdown of IGFBP-5 slightly reduced the apoptosis induced by curcumin. Promoter deletion mapping further identified the region between nt-71 and -59 from the transcription start site, where contains C/EBPα-binding element, is indispensable for curcumin-mediated IGFBP-5 up-regulation. Chromatin immunoprecipitation assays revealed that in vivo binding of C/EBPαto this region was remarkably increased upon treatment with curcumin, whereas curcumin slightly induced C/EBPα expression. Curcumin up-regulates IGFBP-5 and C/EBPα expression through p38MAPK activation, which is abrogated by SB253580 treatment. MKK6 expression activates p38 and C/EBPα, and up-regulates IGFBP-5 expression. The findings indicate that curcumin activates p38MAPK, which in turn activates C/EBPα transactivator to interact with binding elements in IGFBP-5 promoter. The consequential up-regulation of IGFBP-5 could be important for the suppression of oral carcinogenesis.