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

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 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-

EGF Up-Regulates miR-31 through the C/EBPβ Signal Cascade in Oral Carcinoma

“…It mediates pluripotency by inhibiting various oncogenic signaling pathways including AKT, ß-catenin, Bcl2, ERK, NFκB and others [37], some of which seem to be involved in counteracting EGFR stimulation. Furthermore, curcumin activates p38/MAPK bringing about C/EBPα up-regulation in oral keratinocytes, which results in tumor suppression [31]. In this study, we identified for the first time that EGF is an oncogenic factor that is able to up-regulate miR-31 expression in OSCC cells.…”

“…These proteins are members of the basic leucine zipper transcription factor group and are important mediators of various physiological and pathological states including tumorigenesis [29]. C/EBPα plays a suppressor role in OSCC and other keratinocytic malignancies by maintaining cellular homeostasis [30], [31]. Various lines of evidence indicate that C/EBPβ is an oncogenic factor.…”

Biological and therapeutic activities, and anticancer properties of curcumin

“…In SAS oral cancer cells, curcumin induced the promoter activity of insulin-like growth factor binding protein-5 and CCAAT/enhancer-binding protein α, which are involved in the suppression of head and neck cancer. Curcumin exerted an inhibitory effect on these factors through the activation of p38, and resulted in decreased in vivo tumorigenesis in a mouse xenograft model (85). The activity of curcumin has been investigated in a number of head and neck SCC (HNSCC) cell lines, including CAL27, CCL23 (laryngeal), UM-SCC1 and UMSCC14A (oral) (86).…”

“…Clark et al observed an inhibited tumor growth in mice, via the inhibition of the AKT/MTOR pathway, following treatment with an oral curcumin solution prior to inoculation of SCC40 tongue SCC cells (102). In addition, Chang et al demonstrated the suppression of oral carcinogenesis in mice xenografts (85). Furthermore, Kumar et al (103) developed a novel class of curcumin analogs (H-4073), based on diarylidenylpiperidones (DAP), incorporating a piperidone link to the β-diketone structure and fluoro-substitutions on the phenyl groups.…”

Novel Acridine-Based <i>N</i>-Acyl-homoserine Lactone Analogs Induce Endoreduplication in the Human Oral Squamous Carcinoma Cell Line SAS

“…The optimal inhibitor concentrations were determined according to previous studies. 19,20) Statistical Analysis Each experiment was performed at least 3 times. Differences between the control and experimental groups were evaluated by the Mann-Whitney's U-test, the Student's t-test, or the Scheffé's F-test.…”