Endoplasmic reticulum stress stimulates the expression of cyclooxygenase-2 through activation of NF-κB 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, Ming Derg Lai

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182 Citations (Scopus)

Abstract

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-κB and activation of pp38 MAPK were observed during ER stress. IκBα kinase inhibitor Bay 11-7082 or IkBα kinase dominant negative mutant significantly inhibited the induction of COX-2. pp38 MAPK inhibitor SB203580 or eIF2α phosphorylation inhibitor 2-aminopurine attenuated the nuclear NF-κB 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-κB and pp38 kinase pathways. Our results provide important insights into cellular carcinogenesis associated with latent endoplasmic reticulum stress.

Original languageEnglish
Pages (from-to)46384-46392
Number of pages9
JournalJournal of Biological Chemistry
Volume279
Issue number45
DOIs
Publication statusPublished - Nov 5 2004
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry

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  • Cite this

    Hung, J. H., Su, I. J., Lei, H. Y., Wang, H. C., Lin, W. C., Chang, W. T., Huang, W., Chang, W. C., Chang, Y. S., Chen, C. C., & Lai, M. D. (2004). Endoplasmic reticulum stress stimulates the expression of cyclooxygenase-2 through activation of NF-κB and pp38 mitogen-activated protein kinase. Journal of Biological Chemistry, 279(45), 46384-46392. https://doi.org/10.1074/jbc.M403568200