Epigallocatechin-3-gallate and tolfenamic acid induces apoptosis and growth inhibition in head and neck cancer : Involvement of NSAID activated gene-1

With over 500,000 cases worldwide and a high mortality rate, head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer in men. The 5-year overall survival rate for patients with advanced HNSCC is around 30%, which is essentially unchanged from the rate recorded two decades ago in spite of various treatment trials. Therefore, preventive strategies are desirable, and much research is currently devoted to chemoprevention that aims to prevent HNSCC progression at an early stage. However, which chemopreventive agents are the safest and most effective against HNSCC remains unclear. It is of clinical importance to investigate the efficacy of anti-oxidant and nonsteroidal anti-inflammatory drugs (NSAIDs) as chemopreventive agents. At present, the chemopreventive agents that have been most widely investigated as chemopreventive agents are NSAIDs and anti-oxidants.Epigallocatechin-3-gallate (EGCG), a major polyphenolic constituent of green tea, possesses remarkable chemopreventive and therapeutic potential against various types of cancer, including HNSCC. In addition to, NSAIDs have been clinically used as chemopreventive agents for familial adenomatous polyposis, with the mode of action being the inhibition of cyclooxygenase-2 (COX-2). However, chemopreventive and antitumorigenic activities of NSAIDs have also been observed in COX-2-deficient cells, indicating that NSAIDs also exert their anticancer effect through a mechanism other than COX-2 suppression. One such mechanism involves the induction of NSAID-activated gene-1 (NAG-1). Non-steroidal anti-inflammatory drug-activated gene-1 (NAG-1), a TGF-β superfamily protein, is shown to be induced by several anti-tumorigenic compounds and to exhibit pro-apoptotic and anti-tumorigenic activities. In this study, NAG-1 induction during tolfenamic acid or EGCG induced apoptosis was evaluated to determine if they were involved in their anti-cancer activity on HNSCC. Both of the compounds reduced HNSCC viability and induced apoptosis in a dose-dependent manner. The induced apoptosis was coincident with the expression of NAG-1. Overexpression of NAG-1 enhanced the apoptotic effect of EGCG and tolfenamic acid, whereas suppression of NAG-1expression by small interfering RNA attenuated apoptosis. Also we identified that p53 is required for EGCG- mediated activation of NAG-1 by reporter assays using the luciferase constructs containing the NAG-1 promoter. Subsequently, we found that ataxia telangiectasia mutated (ATM) plays an important role in activating these pro-apoptotic proteins (NAG-1 and p53) and cell cycle inhibitor (p21). Furthermore, the antitumor effects of EGCG and tolfenamic acid was observed in tumor-bearing xenograft and syngeneic mouse models which is accompanied with induction of apoptotic cells and NAG-1 expression in tumor tissue samples. The results of this study revealed for the first time that EGCG and tolfenamic acid induces apoptosis via NAG-1 expression in HNSCC. Especially we identified that EGCG induced NAG-1 expression is dependent with ATM/p53. These results present an additional mechanism for antitumor effects of EGCG and tolfenamic acid.

Author dc:creator

• 강, 성운

Contributors dc:contributor

• 김, 철호
• 대학원 의생명과학과
• 106188

• EGCG
• Tolfenamic acid
• NAG-1
• p53
• head and neck cancer
• apoptosis
• ATM

Language dc:language

en

Identifier

http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000013428
000000013428

OAI identifier oai:identifier

oai:repository.ajou.ac.kr:201003/8579