Mechanisms of anti-proliferative effect of JTE-522, a selective cyclooxygenase-2 inhibitor, on human liver cancer cells.
Selective cyclooxygenase-2 (COX-2) inhibitors have been demonstrated to inhibit the proliferation of a variety of cancer cells including hepatocellular carcinoma (HCC). We sought to explore the mechanisms by which JTE-522, a selective COX-2 inhibitor, suppressed the growth of human HCC cells. HCC cells (HepG2, HLF, huH1, Huh7, and PLC/PRF/5 cells) did not express COX-2 at either the mRNA or protein level. Prostaglandin E2 (PGE2) levels in medium were not significantly modulated by the JTE-522 treatment. However, MTT assays disclosed that escalating doses (100 nM to 100 microM) of JTE-522 significantly inhibited the growth of all HCC cells in a dose- and time-dependent manner. JTE-522 induced cell cycle arrest at the G1 phase, which was in part mediated by downregulation of cyclin E. Hallmarks of apoptosis, including the sub-G1 fraction by flow cytometric analysis and nuclear fragmentation by nuclear staining, were not significantly induced after the JTE-522 treatment. In addition, JTE-522 enhanced the expression of peroxisome proliferator-activated receptor (PPAR)-gamma protein in HepG2 and PLC/PRF/5 cells. Our data demonstrate that JTE-522 inhibited the growth of HCC cells in a COX-2-independent manner, and that the growth inhibition was in part mediated by the cell cycle arrest and the upregulation of PPAR-gamma protein.
Nagahara
Takakazu
T
Second Department of Internal Medicine, Tottori University School of Medicine, 36-1 Nishi-cho, Yonago, Tottori 683-8504, Japan.
Okano
Jun-ichi
J
Murawaki
Yoshikazu
Y
D017209:Apoptosis / Q000187:drug effects; D001557:Benzenesulfonates / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D056741:Cyclin D; D019927:Cyclin E / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000737:chemistry* / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D015513:Oncogene Proteins / Q000378:metabolism; D010080:Oxazoles / Q000494:pharmacology*; D047495:PPAR gamma / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects; D000096926:Benzenesulfonamides
D001557:Benzenesulfonates; D020169:Caspases; D056741:Cyclin D; D019927:Cyclin E; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D015232:Dinoprostone; D020928:Mitogen-Activated Protein Kinases; D015513:Oncogene Proteins; D010080:Oxazoles; D047495:PPAR gamma; C110453:4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide; D000096926:Benzenesulfonamides; C475820:CCNE1 protein, human; C496540:PTGS2 protein, human