title: Expression of NSAID-activated gene-1 by EGCG in head and neck cancer: involvement of ATM-dependent p53 expression.
abstract: Epigallocatechin-3-gallate (EGCG), a major polyphenolic constituent of green tea, possesses remarkable chemopreventive and therapeutic potential against various types of cancer, including head and neck squamous cell carcinoma (HNSCC). However, the molecular mechanism involved is not completely understood. Nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1), a transforming growth factor β superfamily protein, is shown to be induced by several antitumorigenic compounds and to exhibit proapoptotic and antitumorigenic activities. In this report, we demonstrate that EGCG transcriptionally induced the expression of NAG-1 during EGCG-induced apoptosis of HNSCC cells. Reporter assays, using the luciferase constructs containing the NAG-1 promoter, demonstrate that p53 is required for EGCG-mediated activation of NAG-1. Overexpression of NAG-1 enhanced the apoptotic effect of EGCG, whereas suppression of NAG-1 expression by small interfering RNA attenuated EGCG-induced apoptosis in HNSCC cells. Subsequently, we found that ataxia-telangiectasia mutated (ATM) plays an important role in activating these proapoptotic proteins (NAG-1 and p53) and cell cycle inhibitor (p21). Furthermore, EGCG significantly inhibited tumor formation as assessed by xenograft models, and this result is accompanied with induction of apoptotic cells and NAG-1 expression in tumor tissue samples. Taken together, these results demonstrate for the first time that EGCG induces apoptosis via ATM/p53-dependent NAG-1 expression in HNSCC, providing an additional mechanistic explanation for the apoptotic activity of EGCG.
authors.affiliation: Department of Otolaryngology, Ajou University School of Medicine, 5 Wonchon-Dong, Yeongtong-Gu, Suwon 442-749, Korea.
authors.forename: Sung Un
authors.initials: SU
authors.lastname: Kang
authors.forename: Bok-Soon
authors.initials: BS
authors.lastname: Lee
authors.forename: Seong-Ho
authors.initials: SH
authors.lastname: Lee
authors.forename: Seung Joon
authors.initials: SJ
authors.lastname: Baek
authors.forename: Yoo Seob
authors.initials: YS
authors.lastname: Shin
authors.forename: Chul-Ho
authors.initials: CH
authors.lastname: Kim
mesh_terms: D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics* / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D055436:Growth Differentiation Factor 15 / Q000235:genetics*; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D034741:RNA, Small Interfering / Q000378:metabolism; D000077195:Squamous Cell Carcinoma of Head and Neck; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D016588:Anticarcinogenic Agents; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D002392:Catechin; C045651:epigallocatechin gallate; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins