Effects of oral consumption of the green tea polyphenol EGCG in a murine model for human Sjogren's syndrome, an autoimmune disease.

SIGNIFICANCE: Protection of glandular cells from autoimmune-induced damage would be of significant clinical benefit to Sjogren's syndrome (SS) patients. Epigallocatechin-3-gallate (EGCG) possesses anti-apoptotic, anti-inflammatory, and autoantigen-inhibitory properties. AIMS: To investigate if EGCG protects against certain autoimmune-induced pathological changes in the salivary glands of the non-obese diabetic (NOD) mouse model for SS. MAIN METHODS: Animals were provided with either water or water containing 0.2% EGCG. At the age of 8, 16 and 22 weeks, submandibular salivary gland tissue and serum samples were collected for pathological and serological analysis. KEY FINDINGS: Significant lymphocyte infiltration was observed in the salivary glands of the water-fed group at the age of 16 weeks, while the EGCG group showed reduced lymphocyte infiltration. By 22 weeks of age, water-fed animals demonstrated elevated levels of apoptotic activity within the lymphocytic infiltrates, and high levels of serum total anti-nuclear antibody, compared to EGCG-fed animals. Remarkably, proliferating cell nuclear antigen (PCNA) and Ki-67 levels in the salivary glands of water-fed NOD mice were significantly elevated in comparison to BALB/c control mice; in contrast, PCNA and Ki-67 levels in EGCG-fed NOD animals were similar to BALB/c mice. These results indicate that EGCG protects the NOD mouse submandibular glands from autoimmune-induced inflammation, and reduces serum autoantibody levels. Abnormal proliferation, rather than apoptosis, appears to be a characteristic of the NOD mouse gland that is normalized by EGCG. The evidence suggests that EGCG could be useful in delaying or managing SS-like autoimmune disorders.

Influence of matrix-suspended demineralized bone on osseous repair using a critical-sized defect in the rat (Rattus norvegicus) calvarium.

Demineralized freeze-dried bone (DFDB) in matrix form must be rehydrated with a carrier medium which allows for easy manipulation during periodontal surgery. The purpose of this study was to evaluate how human DFDB suspended in a polyol matrix affects new bone formation in the rat calvarium critical-sized defect (CSD) model. Fifty-five adult male Harlan Sprague-Dawley rats were assigned to 1 of 5 treatment groups: polyol, 100% DFDB, 47% DFDB/polyol, 47% DFDB, or an unfilled control. They were then placed into 8-m calvarial CSDs. The bone donor source company for the DFDB and DFDB/polyol groups was the same. Calvaria were harvested 10 weeks after surgery and evaluated histomorphometrically. The diameter of bone particles from the 3 groups containing DFDB was measured by scanning electron microscopy. There was no statistically significant difference in the percentage of bone fill between any of the groups, although the 100% DFDB group exhibited the most bone fill. The 47% DFDB/polyol and 47% DFDB groups had similar amounts of bone formation. The average size of the demineralized bone particles from the 100% DFDB group was significantly smaller than that of the other 2 groups containing DFDB. Adding a polyol to DFDB produced similar osseous regeneration in the rat calvarium defect model vs DFDB alone. Yet from a clinical standpoint, the polyol enhanced graft handling and stability. Graft particle size may have an effect on bone fill.

Green tea polyphenols reduce autoimmune symptoms in a murine model for human Sjogren's syndrome and protect human salivary acinar cells from TNF-alpha-induced cytotoxicity.

Sjogren's syndrome (SS) is a relatively common autoimmune disorder. A key feature of SS is lymphocytic infiltration of the salivary and lacrimal glands, associated with the destruction of secretory functions of these glands. Current treatment of SS targets the symptoms but is unable to reduce or prevent the damage to the glands. We reported previously that the major green tea polyphenol (GTP) epigallocatechin-3-gallate (EGCG) inhibits autoantigen expression in normal human keratinocytes and immortalized normal human salivary acinar cells (Hsu et al. 2005). However, it is not known whether GTPs have this effect in vivo, if they can reduce lymphocytic infiltration, or protect salivary acinar cells from tumor necrosis factor-alpha (TNF-alpha)-induced cytotoxicity. Here, we demonstrate that in the NOD mouse, a model for human SS, oral administration of green tea extract reduced the serum total autoantibody levels and the autoimmune-induced lymphocytic infiltration of the submandibular glands. Further, we show that EGCG protected normal human salivary acinar cells from TNF-alpha-induced cytotoxicity. This protection was associated with specific phosphorylation of p38 MAPK, and inhibitors of the p38 MAPK pathway blocked the protective effect. In conclusion, GTPs may provide a degree of protection against autoimmune-induced tissue damage in SS, mediated in part through activation of MAPK elements.

Efficacy of two contemporary single-cone filling techniques in preventing bacterial leakage.

This in vitro study evaluated the sealing efficacy of three root-filling systems/techniques in preventing bacterial leakage. Instrumented single-rooted root segments were filled with (1) warm vertical compaction with gutta-percha/AH Plus; (2) single-cone technique with ActiV GP; and (3) single-cone technique with Gutta-Flow. A dual-chamber leakage model using S. mutans as a microbial marker was used for leakage evaluation. Bacterial penetration was monitored over a 100-day period. Leakage was recorded when turbidity was observed in the lower chamber. Gutta-percha warm vertical compaction exhibited the best seal with bacterial leakage observed in only 16.7% of the specimens between 59 and 100 days. All ActiV GP specimens leaked between 7 and 100 days; 50% of the Gutta-Flow specimens leaked between 22 and 100 days. The two contemporary single-cone techniques did not insure a durable apical seal against bacterial leakage. A warm vertical compaction technique using thermoplasticized gutta-percha and AH Plus sealer appears to be more effective in minimizing bacterial leakage.

Expression of caspase-14 reduces tumorigenicity of skin cancer cells.

BACKGROUND: The green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) possesses anti-carcinogenic properties and was found to induce terminal differentiation in epidermal keratinocytes. Caspase-14, a member of the caspase family associated with epithelial cell differentiation, planned cell death, and barrier formation, is induced by EGCG in normal human epidermal keratinocytes but not in cancer cells. MATERIALS AND METHODS: A human epidermoid cancer cell line, A431, was co-transfected with a caspase-14-expressing pCMV vector and a GFP/neo-etpressingpCMVvector. Cell growth and tumorigenicity of the stable transfectant were determined in comparison to cells transfected with the control GFP/neo-expressing pCMV vector. RESULTS: Expression of exogenous caspase-14 led to growth inhibition and reduced the tumorigenicity of A431 cells. CONCLUSION: Pending future studies, caspase-14 could be used as a novel approach to skin cancer therapy via gene delivery systems.

Reduction in antimicrobial substantivity of MTAD after initial sodium hypochlorite irrigation.

Potential intrinsic tetracycline staining of intraradicular dentin has been observed when BioPure MTAD was employed as the final irrigant after initial rinsing with NaOCl. This study examined the effect of NaOCl-MTAD interaction on the antimicrobial substantivity of MTAD in dentin. Dentin cores previously irrigated with either MTAD, or in conjunction with 1.3% NaOCl as an initial irrigant were placed on blood agar plates inoculated with Escherichia faecalis at 10(5) cfu/ml. Dentin cores irrigated with 1.3% NaOCl only, and autoclaved dentin disks were used as the respective positive and negative controls. After anaerobic incubation, the mean diameter of bacterial inhibition zones formed around the MTAD group was significantly larger than the NaOCl/MTAD group, which, in turn, was not significantly different from the NaOCl positive control. Oxidation of MTAD by NaOCl resulted in the partial loss of antimicrobial substantivity in a manner similar to the peroxidation of tetracycline by reactive oxygen species.

Penetration of fluids into periodontal pockets using a powered toothbrush/irrigator device.

UNLABELLED: This study was a single-blind, randomized, controlled clinical trial. The researchers evaluated a powered brush/irrigating device (HydraBrush Oral Health System; OHS) for its safety and ability to deliver a solution to the bottom of 5-6 mm pockets, compared to rinsing alone with a solution following brushing with a powered toothbrush (Sonicare Elite 7800; SE). An evaluation technique to measure the quantity and quality of solution able to enter the pocket was also introduced in this project. METHODS: Subjects were randomized in one of two-groups: brush plus simultaneous irrigation (OHS) versus brush plus rinsing (SE). Subjects used their devices at home for two weeks. At the measurement visit, subjects used the OHS to irrigate and brush simultaneously for 1 minute (30 seconds per each side of the mouth) with a 0.01% erythrosine disclosing solution in 10 oz of distilled water. Control subjects brushed for 2 minutes with a SE followed by a 1 minute rinse with an identical disclosing solution. A blinded evaluator collected six samples of approximately of 1 microL of sucular fluid from six 5-6 mm evaluation sites. This was accomplished by inserting a microcapillary tip with a 20 microL micropipette in the sulcus. Two-group repeated measures ANOVA was used to examine differences in two measures of the disclosing solution between OHS and SE subjects; the spectrometer reading of the disclosing solutions, and by visual inspection of the samples (positive/negative) to determine the presence or absence of solution in the samples. Subjects' diaries were collected. Bleeding and discomfort during the evaluation period was reported. RESULTS: Visually, OHS had a significantly greater proportion of solution taken from the base of 5-6 mm sites than the SE (p=0.0001). However, there was no statistical difference between the two groups (p=.1359) in the spectrophotometer readings. CONCLUSION: The experimental device is more efficient in delivering a solution to the base of 5-6 mm pockets than rinsing following use of a control powered toothbrush. Both devices have demonstrated they are safe and well accepted by patients. The technique developed provides a useful method for quantitative and qualitative studies of solutions from the base of periodontal pockets.

Role of p21WAF1 in green tea polyphenol-induced growth arrest and apoptosis of oral carcinoma cells.

The cyclin-dependent kinase inhibitor p21WAF1 participates in cell growth, differentiation, and apoptosis. p21WAF1 can be induced by green tea polyphenol EGCG in several cancer cell types, but its role in the oral cancer cell response to EGCG is not known. We found that EGCG upregulates p21WAF1 in an oral carcinoma cell line, OSC2, by cDNA microarray. The current study determined the impact of siRNA-suppressed p21WAF1 and its response to EGCG on cell growth, DNA synthesis and apoptosis by RT-PCR, Western blot, BrdU incorporation, MTT and caspase 3 activity assays. Suppression of p21WAF1 by siRNA resulted in an accelerated cell growth and DNA synthesis, and increased cell viability. However, caspase 3 activity was not significantly inhibited. The evidence showed that p21WAF1 is involved in EGCG-induced growth arrest of OSC2 cells, which may facilitate caspase 3-mediated apoptosis. Thus, expression of functional p21WAF1 may promote phytochemical-mediated growth arrest and apoptosis in oral carcinoma cells.

A mechanism-based in vitro anticancer drug screening approach for phenolic phytochemicals.

Plant-derived phenolic compounds, including polyphenols (e.g., tannins), flavonoids, and phenolic acids, have been under investigation for their anticancer therapeutic and chemoprevention properties. Recently, certain mechanisms underlying the differential effects of green tea polyphenols (GTPPs) on tumor versus normal cells have been determined. These suggest that GTPPs may simultaneously activate multiple pathways. However, existing screening methods are insufficient for the identification of agents that possess both a cytotoxic effect on tumor cells and a protective effect on normal cells. The current study describes the establishment of an in vitro survival/apoptosis testing system based on detecting these mechanisms by a double-fluorescence method. This system is able to screen potential chemopreventive or therapeutic agents from (but not limited to) plant-derived compounds based on the pathways differentially activated by the agents. Tumor cell death and normal cell survival are detected simultaneously, in a device that co-cultures normal human cells adjacent to human tumor cells.

Induction of apoptosis in oral cancer cells: agents and mechanisms for potential therapy and prevention.

Oral cancer is one of the most disfiguring types of cancer, since the surgical removal of the tumor may result in facial distortion. Oral cancer is also known to exhibit "field cancerization", resulting in the development of a second primary tumor. Furthermore, the five-year survival rate of this disease has remained approximately 50% during the past 30 years. Prevention and early detection/treatment of oral cancer could significantly improve the quality of life for individuals at risk. Recently, the targeted elimination of oral squamous cell carcinoma cells by inducing apoptosis has emerged as a valued strategy to combat oral cancer. Studies utilizing a variety of chemical or biological interventions demonstrated promising results for induction of apoptosis in oral malignant cells. This review summarizes the results of a number of investigations focused specifically on induction of apoptosis in oral cancer cells by synthetic compounds and naturally occurring chemopreventive agents with apoptotic potential.

Protective effects of EGCG on salivary gland cells treated with gamma-radiation or cis-platinum(II)diammine dichloride.

Dysfunction of salivary glands is often associated with aging and cancer therapy. Green tea polyphenols were previously found to protect normal epithelial cells from reactive oxygen species, and to induce apoptosis in tumor cells. The current study investigated whether -(-) epigallocatechin-3-gallate (EGCG), the major green tea polyphenol, protects normal salivary gland cells from the effects of gamma-irradiation and the chemotherapy drug cis-platinum(II)diammine dichloride (CDDP). Human immortalized salivary acinar and ductal cells, and oral squamous cell carcinoma cells were irradiated with gamma-rays or treated with CDDP, with or without pretreatment with EGCG, followed by MTT and BrdU incorporation assays. The results demonstrated that EGCG protected the normal salivary gland cells from chemical or irradiation-induced damage. However, protection of oral cancer cells by EGCG was also observed if EGCG was at physiologically achievable salivary concentrations but not at higher concentrations, suggesting that the combination of green tea consumption with cancer therapy requires further evaluation.

Green tea polyphenol targets the mitochondria in tumor cells inducing caspase 3-dependent apoptosis.

Induction of apoptosis by green tea polyphenols has been observed in various tumor cell systems, but whether green tea polyphenol-induced apoptosis requires caspase 3 for execution has not been confirmed. We previously reported that green tea polyphenol-induced apoptosis involved Apaf-1 accumulation and caspase 3 activation in the cytosol. In the current study, tumor cells either with deleted caspase 3 gene or expressing wild-type caspase 3 were treated with increasing concentrations of green tea polyphenol(s), followed by morphological analysis and caspase 3 activity assay. The caspase 3 null parental cell line was further examined in comparison with a well-characterized, caspase 3 wild type oral carcinoma cell line by MTT assay and BrdU incorporation assay. The results demonstrated that, while the mitochondrial function gradually declined to insignificant levels, caspase 3 null cells did not undergo apoptosis, which suggested that green tea polyphenol-induced apoptosis is a mitochondria-targeted, caspase 3-executed mechanism.

Induction of p57 is required for cell survival when exposed to green tea polyphenols.

Green tea polyphenols (catechins) are known to induce cell death in many types of tumor cells, but how normal epithelial cells survive in the presence of polyphenols is unknown. We recently reported that green tea polyphenols potently induced a cyclin-dependent kinase inhibitor, p57/(KIP2), only in normal human epithelial cells. In this study, we investigated the correlation between p57 expression and survival/apoptosis by Western blot analysis, caspase 3 assays and morphological analysis. It was demonstrated that, in the cells that lack p57 induction, green tea polyphenols induced Apaf-1 expression along with caspase 3 activation, leading to apoptosis. In contrast, cells with polyphenol-inducible p57 maintained constant levels of Apaf-1 and proliferating cell nuclear antigen (PCNA), with basal caspase 3 activity. Retroviral-transfected, p57-expressing oral carcinoma cells showed significant resistance to green tea polyphenol-induced apoptosis. Our results suggest that p57/KIP2 is a determinant pro-survival factor for cell protection from green tea polyphenol-induced apoptosis.

Alterations of cell lipids by metal salts.

Metallic medical devices undergo degradation in vivo and the degradation products affect the chemistry and biological responses of cells and tissues in the immediate vicinity. The responses vary with the metal and cell type. In the current study, we examined the effects of several metals on a human monocytic cell line. Monocytes are important effector cells capable of responding rapidly to inflammatory and immune stimuli in a variety of ways, including production of inflammatory proteins, differential expression of surface adhesion molecules, enhanced phagocytic activity, and activation and differentiation to macrophages. Cells were exposed in the presence of (14)C-acetate to titanium, nickel, chromium, copper, or cobalt or vanadium at concentrations that were subinhibitory or inhibitory based on cellular mitochondrial dehydrogenase activity. Cell lipids were then extracted, separated by thin layer chromatography, and quantitated by liquid scintillation spectrometry. Total cell protein also was measured. Titanium reduced cell protein content at concentrations that were noninhibitory to mitochondrial dehydrogenase activity, whereas neither chromium nor cobalt affected protein amounts at dehydrogenase-inhibitory concentrations. In cells exposed to vanadium, the protein- and dehydrogenase-inhibitory concentrations were similar. The major effects on cell lipids appeared to occur in the neutral lipids, although chromium, cobalt, and titanium produced changes in some major phospholipids. These results suggest that metals differentially affect various metabolic pathways in THP-1 cells, perhaps related to their abilities to enter the cells or interact with the membrane. These alterations to the cells may affect the cells' abilities to respond to various stimuli that can damage the tissues.

Vascular responsiveness to dimethylaminoethyl methacrylate and its degradation products.

The increasing use of acrylate-based resins in dentistry has raised questions about the biocompatibility of these substances with oral tissues. The focus of the present investigation was to assess the responsiveness of blood vessels to the resin polymerization accelerating agent dimethylaminoethyl methacrylate (DMAEMA) and its degradation products dimethylethanolamine (DME) and methacrylic acid (MAA), using the rat aortic ring preparation as a tissue model. DMAEMA induced concentration-dependent relaxation of norepinephrine (NE)-contracted aortic rings with and without endothelium. N-nitro-L-arginine methyl ester (L-NAME) selectively inhibited the endothelium-dependent relaxation induced by DMAEMA, suggesting the release of nitric oxide from the endothelium by DMAEMA. Both indomethacin and glybenclamide attenuated the vasorelaxation elicited by DMAEMA in the presence as well as in the absence of endothelium, providing evidence for the role of vasorelaxant prostanoid(s) and K(ATP) channel activation in the responses observed. On the other hand, while MAA was without any apparent effect on the rat aorta, DMAEMA at high and DME at relatively low concentrations caused contraction of the tissues with and without endothelium in the absence of NE. The DME-induced contraction was inhibited by indomethacin, suggesting the involvement of contractile arachidonic acid metabolite(s) in the action of DME. This observation was supported by the findings of increased thromboxane A(2) (TXA(2)) production in aortic rings incubated with DME. Taken together, the data suggest that both DMAEMA and its degradation product, DME, are vasoactive, inducing vasorelaxation and contraction by various mechanisms that may involve the release of nitric oxide from the endothelium, the activation of smooth muscle K(ATP) channels, and the generation of vasorelaxant prostanoid(s) and TXA(2). These effects may play a role in tissue homeostasis and certain adverse conditions associated with the use of dental resin materials containing DMAEMA and/or DME.

Nicotine modulation of in vitro human gingival fibroblast beta1 integrin expression.

BACKGROUND: Smoking is clearly a high-risk behavior for the development of periodontal disease, and nicotine is the major vasoactive component in tobacco. Integrins are a large family of homologous transmembrane adhesion proteins serving as the principal receptors on animal cells to bind and communicate with many extracellular matrix proteins such as collagen, fibronectin, and laminin. This study's aim was to evaluate nicotine's effects on beta1 integrin expression as a function of either 1) the generalized effects on RNA/protein synthesis or 2) as a specific modulation of beta1 integrin synthesis. METHODS: Pooled human gingival fibroblasts (HGFs) were cultured in nicotine concentrations commonly seen in smokers (0.025 to 0.8 microM), and relative incorporation of [35S]methionine into newly synthesized protein or [3H]uridine into newly synthesized RNA was measured. Cultures were harvested at various times, and duplicate cell aliquots were homogenized and fractionated to obtain cell membrane-enriched preparations or solubilized to obtain whole cell lysates. Radiolabeled RNA and proteins were quantitated by trichloroacetic acid (TCA) precipitation and liquid scintillation spectrometry. Beta1 integrin subunits were detected by SDS-PAGE and Western blotting, and the relative intensities of reactive bands were quantitated by scanning densitometry. RESULTS: After 17 hours of exposure, 0.4 and 0.8 microM nicotine resulted in a dose-dependent increase in beta1 integrin in whole cell lysates, and a decrease in beta1 integrin in the corresponding membrane-enriched fractions. There was also a statistically significant decrease (P < or = 0.05) in radiolabeled proteins in culture. Although there appeared to be a mild, generalized reduction in radiolabeled RNA in nicotine-treated cultures compared to controls, a 1-way analysis of variance showed no statistical significance between values. CONCLUSIONS: Our results suggest that nicotine may induce an altered compartmentalization process in which beta1 integrin molecules are produced, but are not appropriately transferred to the membrane. Nicotine effects on cellular protein synthesis and its modulation of beta1 integrin expression may impair gingival fibroblast ability to adhere to and communicate with one another and with the extracellular matrix, which could impair wound healing and/or exacerbate periodontal disease.

Chemoprevention of oral cancer by green tea.

Green tea has been a popular beverage for many centuries. Only recently, however, has the anti-cancer power of green tea constituents been unveiled. Green tea polyphenols are found to induce apoptosis (programmed cell death) in many types of tumor cells, including oral cancer cells. However, mechanisms that enable normal cells to evade the apoptotic effect still are not understood. In this study, cell growth and invasion assays combined with apoptosis assays were used to examine the effects of green tea extracts, green tea polyphenols, and the most potent green tea polyphenol, (-)-epigallocatechin-3-gallate (EGCG), on normal human keratinocytes and oral carcinoma cells. The results showed that green tea and its constituents selectively induce apoptosis only in oral carcinoma cells, while EGCG was able to inhibit the growth and invasion of oral carcinoma cells. These differential responses to green tea and its constituents between normal and malignant cells were correlated with the induction of p57, a cell cycle regulator. These data suggest that the chemopreventive effects of green tea polyphenols may involve a p57 mediated survival pathway in normal epithelial cells, while oral carcinoma cells undergo an apoptotic pathway. Therefore, regular consumption of green tea could be beneficial in the prevention of oral cancer.

An evaluation of microbiologic contamination on phosphor plates in a dental school.

OBJECTIVE: The objective of this study was to determine if phosphor plates used in predoctoral clinics are microbiologically contaminated and to identify the source of contamination. STUDY DESIGN: Forty-five of 300 phosphor plates (15%) were randomly selected for examination. The plates were pressed into individual blood agar plates, were incubated using standard techniques at 37 degrees C, and were monitored for 72 hours. The number, size, distribution, and variety of resulting colonies were noted. A representative of each type of colony was selected to be Gram stained using the standard technique. RESULTS: Of the plates, 42.2% were uncontaminated, 57.8% yielded bacterial colonies, and 15.6% of those colonies demonstrated hemolytic growth. The hemolytic growth included combined alpha and beta hemolysis and beta only hemolysis. Six colonies were gram-positive rods and 7 were gram-positive cocci. CONCLUSION: Meticulous infection-control techniques are inevitable and continuous reinforcement and training for staff and students are mandatory. Periodic gas sterilization of phosphor plates may be necessary.

Green tea polyphenol induces caspase 14 in epidermal keratinocytes via MAPK pathways and reduces psoriasiform lesions in the flaky skin mouse model.

Psoriasiform lesions are characterized by hyperproliferation and aberrant differentiation of epidermal keratinocytes, accompanied by inflammation, leading to a disrupted skin barrier with an abnormal stratum corneum. The expression and proteolytic processing of caspase 14, a member of the caspase family which is associated with epithelial cell differentiation, planned cell death, and barrier formation, is altered in psoriatic epidermis. We recently reported that human psoriatic tissues lack normal expression of caspase 14 [J Dermatol Sci37 (2005) 61], and caspase 14 is induced by EGCG, a green tea polyphenol (GTP), in exponentially growing normal human epidermal keratinocytes (NHEK) [J Pharmacol Exp Ther315 (2005) 805]. This suggests that GTPs may have beneficial effects on psoriasiform lesions. The current study aimed to determine whether MAPK pathways are required for GTP-induced caspase 14 expression in NHEK and if GTPs can modulate the expression of pathological markers in the psoriasiform lesions that develop in the flaky skin mouse. The results indicate that the p38 and JNK MAPK pathways are required for EGCG-induced expression of caspase 14 in NHEK. Importantly, topical application of 0.5% GTPs significantly reduced the symptoms of epidermal pathology in the flaky skin mice, associated with efficient caspase 14 processing and reduction in proliferating cell nuclear antigen levels. This suggests that GTP-activated pathways may be potential targets for novel therapeutic approaches to the treatment of some psoriasiform skin disorders.

EGCG-targeted p57/KIP2 reduces tumorigenicity of oral carcinoma cells: role of c-Jun N-terminal kinase.

The green tea polyphenol epigallocatechin-3-gallate (EGCG) regulates gene expression differentially in tumor and normal cells. In normal human primary epidermal keratinocytes (NHEK), one of the key mediators of EGCG action is p57/KIP2, a cyclin-dependent kinase (CDK) inhibitor. EGCG potently induces p57 in NHEK, but not in epithelial cancer cells. In humans, reduced expression of p57 often is associated with advanced tumors, and tumor cells with inactivated p57 undergo apoptosis when exposed to EGCG. The mechanism of p57 induction by EGCG is not well understood. Here, we show that in NHEK, EGCG-induces p57 via the p38 mitogen-activated protein kinase (MAPK) signaling pathway. In p57-negative tumor cells, JNK signaling mediates EGCG-induced apoptosis, and exogenous expression of p57 suppresses EGCG-induced apoptosis via inhibition of c-Jun N-terminal kinase (JNK). We also found that restoration of p57 expression in tumor cells significantly reduced tumorigenicity in athymic mice. These results suggest that p57 expression may be an useful indicator for the clinical course of cancers, and could be potentially useful as a target for cancer therapies.