Aspirin and NS-398 inhibit hepatocyte growth factor-induced invasiveness of human hepatoma cells.
Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) activity and are considered to exert antitumor actions in a variety of cancer cells, although the effects are unlikely entirely due to COX inhibition. Because clinical observations suggest that hepatocyte growth factor (HGF) can promote metastasis of hepatoma cells while stimulating tumor invasiveness, we investigated the effect of aspirin and NS-398, a selective COX-2 inhibitor, on HGF-mediated invasiveness of HepG2 human hepatoma cells. HGF stimulated the invasiveness of HepG2 cells in Matrigel cell invasion assay, together with increased expression of matrix metalloproteinase (MMP) 9. Addition of aspirin or NS-398, similar to PD98059, which acts as a specific inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK), an upstream kinase regulating extracellular signal-regulated kinase (ERK)1/2, abrogated such actions of HGF without affecting cell viability. Aspirin and NS-398, in contrast to PD98059, did not suppress ERK1/2 phosphorylation induced by HGF. However, both agents inhibited the kinase activity of ERK1/2 induced by HGF and repressed HGF-induced phosphorylation of 90-kd ribosomal S6 kinase (RSK) and Elk-1, key downstream substrates of ERK1/2, resulting in the suppression of transcriptional activity of Elk-1 as well as nuclear factor kappaB (NF-kappaB) and AP-1, which are involved in MMP-9 gene regulation. In conclusion, our results suggest that aspirin and NS-398 inhibit HGF-induced invasiveness of HepG2 human hepatoma cells through ERK1/2.
Abiru
Seigou
S
First Department of Internal Medicine, Nagasaki University School of Medicine, Japan.
Nakao
Kazuhiko
K
Ichikawa
Tatsuki
T
Migita
Kiyoshi
K
Shigeno
Masaya
M
Sakamoto
Miyuki
M
Ishikawa
Hiroki
H
Hamasaki
Keisuke
K
Nakata
Keisuke
K
Eguchi
Katsumi
K
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D048728:MAP Kinase Kinase Kinase 1; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D008565:Membrane Proteins; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D009578:Nitrobenzenes / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007527:Isoenzymes; D008565:Membrane Proteins; D016328:NF-kappa B; D009578:Nitrobenzenes; D013449:Sulfonamides; D018808:Transcription Factor AP-1; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D017228:Hepatocyte Growth Factor; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D017346:Protein Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human; D020780:Matrix Metalloproteinase 9; D001241:Aspirin; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one