Hsu Stephen, Yamamoto Tetsuya, Borke James, Walsh Douglas S, Singh Baldev, Rao Sushma, Takaaki Kamatani, Nah-Do Nam, Lapp Carol, Lapp David, Foster Emily, Bollag Wendy B, Lewis Jill, Wataha John, Osaki Tokio, Schuster George
Department of Oral Biology and Maxillofacial Pathology, School of Dentistry, AD1443, Medical College of Georgia, Augusta, GA 30912-1126, USA.
J Pharmacol Exp Ther. 2005 Mar;312(3):884-90. doi: 10.1124/jpet.104.076075. Epub 2004 Nov 10.
Epigallocatechin-3-gallate (EGCG), the most abundant polyphenol in green tea, exerts chemopreventive effects by selectively inducing apoptosis in tumor cells. In contrast, EGCG accelerates terminal differentiation in normal human epidermal keratinocytes (NHEK) mediated partially by up-regulation of p57/KIP2, a cyclin-dependent kinase inhibitor that confers growth arrest and differentiation. However, it is unclear if EGCG modulates caspase 14, a unique regulator of epithelial cell terminal differentiation associated with cornification. Here, we examined the effect of EGCG on caspase 14 expression in NHEK and correlated the protein and mRNA expression of p57/KIP2 with those of caspase 14 in either normal keratinocytes or p57/KIP2-expressing tumor cells (OSC2, an oral squamous cell carcinoma cell line). Additionally, paraffin-embedded normal and untreated psoriatic (aberrant keratinization) skin sections from humans were assessed for caspase 14 by immunohistochemistry. In NHEK, EGCG induced the expression of caspase 14 mRNA and protein levels within a 24-h period. The expression of p57/KIP2 in OSC2 cells was adequate to induce caspase 14 in the absence of EGCG; this induction of caspase 14 was down-regulated by transforming growth factor-beta1. In human psoriatic skin samples, caspase 14 staining in the upper epidermis was reduced, especially in nuclear areas. These results suggest that, in addition to p57/KIP2, EGCG-induced terminal differentiation of epidermal keratinocytes involves up-regulation of caspase 14. Further understanding of how EGCG modulates cellular differentiation may be useful in developing green tea preparations for selected clinical applications.
表没食子儿茶素-3-没食子酸酯（EGCG）是绿茶中含量最丰富的多酚，通过选择性诱导肿瘤细胞凋亡发挥化学预防作用。相比之下，EGCG通过部分上调p57/KIP2加速正常人表皮角质形成细胞（NHEK）的终末分化，p57/KIP2是一种细胞周期蛋白依赖性激酶抑制剂，可导致生长停滞和分化。然而，尚不清楚EGCG是否调节半胱天冬酶14，这是一种与角质化相关的上皮细胞终末分化的独特调节因子。在此，我们研究了EGCG对NHEK中半胱天冬酶14表达的影响，并将p57/KIP2的蛋白质和mRNA表达与正常角质形成细胞或表达p57/KIP2的肿瘤细胞（OSC2，一种口腔鳞状细胞癌细胞系）中的半胱天冬酶14的表达相关联。此外，通过免疫组织化学评估人石蜡包埋的正常和未经治疗的银屑病（异常角质化）皮肤切片中的半胱天冬酶14。在NHEK中，EGCG在24小时内诱导半胱天冬酶14 mRNA和蛋白质水平的表达。在没有EGCG的情况下，OSC2细胞中p57/KIP2的表达足以诱导半胱天冬酶14；转化生长因子-β1下调了这种对半胱天冬酶14的诱导。在人银屑病皮肤样本中，上表皮中的半胱天冬酶14染色减少，尤其是在核区域。这些结果表明，除了p57/KIP2之外，EGCG诱导的表皮角质形成细胞终末分化涉及半胱天冬酶14的上调。进一步了解EGCG如何调节细胞分化可能有助于开发用于特定临床应用的绿茶制剂。
