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J. Biol. Chem., Vol. 279, Issue 49, 50676-50683, December 3, 2004

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The Induction of Prostaglandin E₂ Production, Interleukin-6 Production, Cell Cycle Arrest, and Cytotoxicity in Primary Oral Keratinocytes and KB Cancer Cells by Areca Nut Ingredients Is Differentially Regulated by MEK/ERK Activation^*

Mei-Chi Chang, Hui-Lin Wu, Jang-Jaer Lee¶, Po-Hsuen Lee, Hsiao-Hwa Chang¶, Liang-Jiunn Hahn¶, Bor-Ru Lin||, Yi-Jane Chen¶, and Jiiang-Huei Jeng¶**

From the Team of Biomedical Science, Chang-Gung Institute of Technology, Kwei-Shan, Taoyuan, Taiwan, the Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan, the ^¶Laboratory of Dental Pharmacology and Toxicology, School of Dentistry, College of Medicine, National Taiwan University Hospital, Taipei, Taiwan, and the ^||Department of Diagnotherapeutics, National Taiwan University Hospital, Taipei, Taiwan

There are about 200–600 million betel quid (BQ) chewers in the world. BQ chewing is one of the major risk factor of hepatocarcinoma, oropharyngeal, and esophagus cancers in Taiwan, India, and Southeast Asian countries. Thus, the precise molecular mechanisms deserve investigation. We used cultured primary keratinocytes and KB cells, RT-PCR, flow cytometry, Western blotting, and ELISA to evaluate whether alterations in early gene expression is crucial in the carcinogenic processes of BQ. We observed the induction of c-Fos mRNA expression in human gingival keratinocyte (GK) and KB carcinoma cells by areca nut (AN) extract and arecoline. A maximal increment in c-fos gene expression was shown at about 30 min after challenge. AN extract (100–800 µg/ml) and arecoline (0.1–0.8 mM) also stimulated ERK1/ERK2 phosphorylation with a maximal stimulation at 5–10 min of exposure. Pretreatment by U0126 (30 µM), a MEK inhibitor, markedly inhibited the c-Fos, cyclooxygenase-2 (COX-2), and IL-6 mRNA expression of the KB epithelial cells. In addition, U0126 and PD98059 (50 µM) also decreased AN extract- and arecoline-associated PGE₂ and IL-6 production in GK and KB cells. However, U0126 by itself arrested the cells in G₀/G₁ phase, but was not able to prevent AN- and arecoline-induced cell death or apoptosis. In contrast, U0126 enhanced the AN-induced apoptosis of KB cells. AN ingredients thus play a significant role in the pathogenesis of oropharyngeal cancer by activation of MEK1/ERK/c-Fos pathway, which promotes keratinocyte inflammation, cell survival, and affects cell cycle progression.

Received for publication, April 22, 2004 , and in revised form, August 11, 2004.

^* This study was supported by a grant from the National Health Research Institute (NHRI-CN-IN-9003S) and National Science Council (NSC90-2314-B002-343), Taiwan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed: Laboratory of Dental Pharmacology & Toxicology, Department of Dentistry, National Taiwan University Hospital & National Taiwan University, College of Medicine, No. 1, Chang-Te Street, Taipei, Taiwan. Fax: 886-2-23821212; E-mail: huei{at}ha.mc.ntu.edu.tw.

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