Endoplasmic reticulum stress stimulates the expression of cyclooxygenase-2 through activation of NF-kappaB and pp38 mitogen-activated protein kinase.
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-kappaB and activation of pp38 MAPK were observed during ER stress. IkappaBalpha kinase inhibitor Bay 11-7082 or IkappaBalpha kinase dominant negative mutant significantly inhibited the induction of COX-2. pp38 MAPK inhibitor SB203580 or eIF2alpha phosphorylation inhibitor 2-aminopurine attenuated the nuclear NF-kappaB 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-kappaB and pp38 kinase pathways. Our results provide important insights into cellular carcinogenesis associated with latent endoplasmic reticulum stress.
Hung
Jui-Hsiang
JH
Department of Biochemistry, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan, Republic of China.
Su
Ih-Jen
IJ
Lei
Huan-Yao
HY
Wang
Hui-Ching
HC
Lin
Wan-Chi
WC
Chang
Wen-Tsan
WT
Huang
Wenya
W
Chang
Wen-Chang
WC
Chang
Yung-Sheng
YS
Chen
Ching-Chow
CC
Lai
Ming-Derg
MD
D021581:Active Transport, Cell Nucleus; D000362:Agar / Q000737:chemistry; D000818:Animals; D015153:Blotting, Western; D020126:Brefeldin A / Q000494:pharmacology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D051546:Cyclooxygenase 2; D003600:Cytosol / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005786:Gene Expression Regulation; D005799:Genes, Dominant; D006515:Hepatitis B virus / Q000235:genetics; D006801:Humans; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors; D007118:Immunoassay; D007527:Isoenzymes / Q000096:biosynthesis*; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D009154:Mutation; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D017510:Protein Folding; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013450:Sulfones / Q000494:pharmacology; D013997:Time Factors; D014018:Tissue Distribution; D014158:Transcription, Genetic; D014415:Tunicamycin / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D015852:Eukaryotic Initiation Factor-2; D020672:I-kappa B Proteins; D007527:Isoenzymes; D008565:Membrane Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D009570:Nitriles; D012333:RNA, Messenger; D013450:Sulfones; D014415:Tunicamycin; D000072000:NF-KappaB Inhibitor alpha; D020126:Brefeldin A; D000362:Agar; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D048051:p38 Mitogen-Activated Protein Kinases