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J. Biol. Chem., Vol. 279, Issue 45, 46384-46392, November 5, 2004

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Endoplasmic Reticulum Stress Stimulates the Expression of Cyclooxygenase-2 through Activation of NF-B and pp38 Mitogen-activated Protein Kinase^*

Jui-Hsiang Hung, Ih-Jen Su¶, Huan-Yao Lei||, Hui-Ching Wang, Wan-Chi Lin, Wen-Tsan Chang, Wenya Huang**, Wen-Chang Chang, Yung-Sheng Chang, Ching-Chow Chen, and Ming-Derg Lai¶¶

From the Department of Biochemistry, the ^||Department of Microbiology and Immunology, Institute of Basic Medicine, the ^**Department of Medical Technology, and the Department of Pharmacology, College of Medicine, National Cheng Kung University, ^¶Division of Clinical Research, National Health Research Institute, Tainan 701, and the Department of Pharmacology, College of Medicine, National Taiwan University, Taipei 100, Taiwan, Republic of China

Expression of mutant proteins or viral infection may interfere with proper protein folding activity in the endoplasmic reticulum (ER). Several pathways that maintain cellular homeostasis were activated in response to these ER disturbances. Here we investigated which of these ER stress-activated pathways induce COX-2 and potentially oncogenesis. Tunicamycin and brefeldin A, two ER stress inducers, increased the expression of COX-2 in ML-1 or MCF-7 cells. Nuclear translocation of NF-B and activation of pp38 MAPK were observed during ER stress. IB kinase inhibitor Bay 11-7082 or IB kinase dominant negative mutant significantly inhibited the induction of COX-2. pp38 MAPK inhibitor SB203580 or eIF2 phosphorylation inhibitor 2-aminopurine attenuated the nuclear NF-B DNA binding activity and COX-2 induction. Expression of mutant hepatitis B virus (HBV) large surface proteins, inducers of ER stress, enhanced the expression of COX-2 in ML-1 and HuH-7 cells. Transgenic mice showed higher expression of COX-2 protein in liver and kidney tissue expressing mutant HBV large surface protein in vivo. Similarly, increased expression of COX-2 mRNA was observed in human hepatocellular carcinoma tissue expressing mutant HBV large surface proteins. In ML-1 cells expressing mutant HBV large surface protein, anchorage-independent growth was enhanced, and the enhancement was abolished by the addition of specific COX-2 inhibitors. Thus, ER stress due either to expression of viral surface proteins or drugs can stimulate the expression of COX-2 through the NF-B and pp38 kinase pathways. Our results provide important insights into cellular carcinogenesis associated with latent endoplasmic reticulum stress.

Received for publication, March 31, 2004 , and in revised form, August 6, 2004.

^* This work was supported in part by Grant NHRI-EX92-9116-BP1 from the National Health Research Institute (to H.-Y. L.) and by the Program for Promoting University Academic Excellence Projects 91-B-FA09–1-4 (to W.-C. C.). 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: Dept. of Biochemistry, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan, Republic of China. Fax: 886-6-2741694; E-mail: a1211207{at}mail.ncku.edu.tw.

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