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

被引:52
作者
Chang, Kuo-Wei [1 ,2 ,3 ]
Hung, Pei-Shih [1 ]
Lin, I-Ying [1 ]
Hou, Chung-Ping [1 ]
Chen, Li-Kai [4 ]
Tsai, Yin-Meng [5 ]
Lin, Shu-Chun [1 ,2 ,3 ]
机构
[1] Natl Yang Ming Univ, Sch Dent, Inst Oral Biol, Taipei 112, Taiwan
[2] Taipei City Hosp, Dept Med Res & Educ, Taipei, Taiwan
[3] Taipei Vet Gen Hosp, Dept Stomatol, Taipei, Taiwan
[4] Taipei City Hosp, Dept Dent, Taipei, Taiwan
[5] Natl Yang Ming Univ, Inst Tradit Med, Taipei 112, Taiwan
关键词
carcinoma; C/EBP alpha; curcumin; IGFBP-5; p38; SQUAMOUS-CELL CARCINOMA; ARECA NUT EXTRACT; NF-KAPPA-B; TUMOR-SUPPRESSOR; RETINOIC ACID; NEUROBLASTOMA-CELLS; DOWN-REGULATION; IN-VITRO; ACTIVATION; DIFFERENTIATION;
D O I
10.1002/ijc.25220
中图分类号
R73 [肿瘤学];
学科分类号
100214 [肿瘤学];
摘要
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.
引用
收藏
页码:9 / 20
页数:12
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