Mechanisms of anti-proliferative effect of JTE-522, a selective cyclooxygenase-2 inhibitor, on human liver cancer cells

作者：Nagahara Takakazu; Okano Jun Ichi^*; Murawaki Yoshikazu

来源：Oncology Reports, 2007, 18(5): 1281-1290.

• hepatocellular carcinoma
• JTE-522
• PPAR-gamma
• selective COX-2 inhibitor

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 mu M) 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.

• 出版日期2007-11