Green Tea Polyphenol and Curcumin Inversely Regulate Human Involucrin Promoter Activity via Opposing Effects on CCAAT/Enhancer-binding Protein Function

Balasubramanian, S.; Eckert, Richard L.

doi:10.1074/jbc.m314331200

Cited by 62 publications

(82 citation statements)

References 60 publications

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“…Keratinocytes were transfected with an involucrin promoter-luciferase reporter plasmid, pINV-241, in which the proximal hINV promoter is linked to luciferase (Balasubramanian et al, 2002;Balasubramanian and Eckert, 2004). Our studies showed that treatment with EGCG for 24 h activates the human involucrin promoter reporter plasmid, pINV-241.…”

Section: Chemopreventive Agents Differentially Regulate Hinv Gene Expmentioning

confidence: 83%

“…Immunoblot studies confirm that EGCG enhances the level of the AP1 factors including Fra-1, Fra-2, c-fos, fosB, Jun-B, Jun-D and c-jun. Moreover, gel supershift analysis reveals that EGCG increases binding of Fra-1 and Jun-D to the hINV promoter AP1-1 site (Balasubramanian et al, 2002;Balasubramanian and Eckert, 2004;.…”

Section: Regulation Of Ap 1 Transcription Factor Functionmentioning

confidence: 97%

“…Our transfection studies using progressively truncated hINV promoter segments showed that the EGCG response element is located in the proximal regulatory region (PRR) spanning nucleotides −128/−110, and mutation analysis showed that the AP1-1 site, located within this region, is required for this regulation (Balasubramanian et al, 2002;Balasubramanian and Eckert, 2004;. Based on these studies, we concluded that EGCG activates hINV gene expression via an AP1 transcription factor-dependent pathway, and that apigenin and curcumin oppose this action (Balasubramanian et al, 2002;Balasubramanian and Eckert, 2004;. Immunoblot studies confirm that EGCG enhances the level of the AP1 factors including Fra-1, Fra-2, c-fos, fosB, Jun-B, Jun-D and c-jun.…”

Section: Regulation Of Ap 1 Transcription Factor Functionmentioning

confidence: 98%

“…Expression of dominant-negative forms of Ras and MEKK1 suppress the EGCG-dependent increase in hINV promoter activity. This indicates that Ras and MEKK1 activity are required for the EGCG-dependent increase in hINV gene expression (Balasubramanian et al, 2002;Balasubramanian and Eckert, 2004). In contrast, apigenin and curcumin treatment inhibit the caRas-and MEKK1-dependent increase in promoter activity.…”

Section: Differential Regulation Of Mapk Signalingmentioning

confidence: 99%

“…To understand these effects, we treated keratinocytes with TPA, a keratinocyte differentiation agent that increases hINV gene expression by increasing AP1 factor level and AP1 factor binding to the hINV promoter AP1 sites (Welter et al, 1995). Both apigenin and curcumin suppress the TPAdependent increase in the level of c-jun, junB, junD, Fra-1, Fra-2 and fos B, and this is associated with decreased AP1 factor binding to the hINV promoter AP1-1 site and reduced promoter activity (Balasubramanian et al, 2002;Balasubramanian and Eckert, 2004;. Proteasome function has been implicated in the regulation of transcription factors in human keratinocytes .…”

Section: Regulation Of Ap 1 Transcription Factor Functionmentioning

confidence: 99%

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Keratinocyte proliferation, differentiation, and apoptosis—Differential mechanisms of regulation by curcumin, EGCG and apigenin

Balasubramanian

Eckert

2007

Toxicology and Applied Pharmacology

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We have proposed that it is important to examine the impact of chemopreventive agents on the function of normal human epidermal keratinocytes, since these cells comprise the barrier that protects the body from a range of environmental insults. In this context, it is widely appreciated that cancer may be retarded by consumption or topical application of naturally-occurring food-derived chemopreventive agents. Our studies show that (−)-epigallocatechin-3-gallate (EGCG), a green teaderived polyphenol, acts to enhance the differentiation of normal human keratinocytes as evidenced by its ability to increase involucrin (hINV), transglutaminase type 1 (TG1) and caspase-14 gene expression. EGCG also stimulates keratinocyte morphological differentiation. These actions of EGCG are mediated via activation of a nPKC, Ras, MEKK1, MEK3, p38δ-ERK1/2 signaling cascade which leads to increased activator protein 1 (AP1) and CAATT enhancer binding protein (C/EBP) transcription factor expression, increased binding of these factors to DNA, and increased gene transcription. In contrast, apigenin, a dietary flavonoid derived from plants and vegetables, and curcumin, an agent derived from turmeric, inhibit differentiation by suppressing MAPK signal transduction and reducing API transcription factor level. Curcumin also acts to enhance apoptosis, although EGCG and apigenin do not stimulate apoptosis. In addition, all of these agents inhibit keratinocyte proliferation. These findings indicate that each of these diet-derived chemopreventive agents has a profound impact on normal human keratinocyte function and that they operate via distinct and sometimes opposing mechanisms. However, all are expected to act as chemopreventive agents. KeywordsEGCG; apigenin; curcumin; TPA; epidermis; involucrin; keratinocyte differentiation; apoptosis; chemoprevention; turmeric Keratinocyte differentiation and human involucrin gene expressionThe keratinocyte is the major cell type of the multilayered stratified squamous epithelium (the epidermis) that covers the body surface. To establish epidermal structure, keratinocytes in the basal layer undergo periodic cell division which gives rise to daughter cells that differentiate

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Section: Chemopreventive Agents Differentially Regulate Hinv Gene Expmentioning

confidence: 83%

Section: Regulation Of Ap 1 Transcription Factor Functionmentioning

confidence: 97%

Section: Regulation Of Ap 1 Transcription Factor Functionmentioning

confidence: 98%

Section: Differential Regulation Of Mapk Signalingmentioning

confidence: 99%

Section: Regulation Of Ap 1 Transcription Factor Functionmentioning

confidence: 99%

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Keratinocyte proliferation, differentiation, and apoptosis—Differential mechanisms of regulation by curcumin, EGCG and apigenin

Balasubramanian

Eckert

2007

Toxicology and Applied Pharmacology

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The combination of epigallocatechin gallate and curcumin suppresses ERα‐breast cancer cell growth in vitro and in vivo

Somers-Edgar

Scandlyn

Stuart

et al. 2008

Intl Journal of Cancer

121

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Both epigallocatechin gallate (EGCG) and curcumin have shown efficacy in various in vivo and in vitro models of cancer. This study was designed to determine the efficacy of these naturally derived polyphenolic compounds in vitro and in vivo, when given in combination. Studies in MDA-MB-231 cells demonstrated that EGCG 1 curcumin was synergistically cytotoxic and that this correlated with G 2 /M-phase cell cycle arrest. After 12 hr, EGCG (25 lM) 1 curcumin (3 lM) increased the proportion of cells in G 2 /M-phase to 263 6 16% of control and this correlated with a 50 6 4% decrease in cell number compared to control. To determine if this in vitro result would translate in vivo, athymic nude female mice were implanted with MDA-MB-231 cells and treated with curcumin (200 mg/kg/day, po), EGCG (25 mg/kg/day, ip), EGCG 1 curcumin, or vehicle control (5 ml/kg/day, po) for 10 weeks. Tumor volume in the EGCG 1 curcumin treated mice decreased 49% compared to vehicle control mice (p < 0.05), which correlated with a 78 6 6% decrease in levels of VEGFR-1 protein expression in the tumors. Curcumin treatment significantly decreased tumor protein levels of EGFR and Akt, however the expression of these proteins was not further decreased following combination treatment. Therefore, these results demonstrate that the combination of EGCG and curcumin is efficacious in both in vitro and in vivo models of ERa-breast cancer and that regulation of VEGFR-1 may play a key role in this effect. ' 2007 Wiley-Liss, Inc.

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

Chang

Hung

Lin³

et al. 2010

Intl Journal of Cancer

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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-

show abstract

Green Tea Polyphenol and Curcumin Inversely Regulate Human Involucrin Promoter Activity via Opposing Effects on CCAAT/Enhancer-binding Protein Function

Cited by 62 publications

References 60 publications

Keratinocyte proliferation, differentiation, and apoptosis—Differential mechanisms of regulation by curcumin, EGCG and apigenin

Keratinocyte proliferation, differentiation, and apoptosis—Differential mechanisms of regulation by curcumin, EGCG and apigenin

The combination of epigallocatechin gallate and curcumin suppresses ERα‐breast cancer cell growth in vitro and in vivo

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

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