Open AccessInvolvement of cell cycle regulatory proteins and MAP kinase signaling pathway in growth inhibition and cell cycle arrest by a selective cyclooxygenase 2 inhibitor, etodolac, in human hepatocellular carcinoma cell lines
Author(s) -
Cheng Jidong,
Imanishi Hiroyasu,
Liu Weidong,
Nakamura Hideji,
Morisaki Takayuki,
Higashino Kazuya,
Hada Toshikazu
Publication year - 2004
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2004.tb03327.x
Subject(s) - cyclin dependent kinase 1 , cyclin a , cell cycle , microbiology and biotechnology , cyclin d1 , cell cycle checkpoint , cyclin d , cyclin dependent kinase , cyclin b1 , protein kinase b , cell growth , cyclin b , restriction point , cyclin dependent kinase 2 , cancer research , mapk/erk pathway , etodolac , biology , kinase , signal transduction , protein kinase a , biochemistry , cell
Recent studies have shown that selective cyclooxygenase‐2 (COX‐2) inhibitors induce growth inhibition and cell cycle arrest in hepatocellular carcinoma (HCC) cell lines. However, the mechanism by which COX‐2 inhibitors regulate the cell cycle and whether or not growth signal pathways are involved in the growth inhibition remain unclear. In this study, we investigated the mechanisms of growth inhibition and cell cycle arrest by etodolac, a selective COX‐2 inhibitor, in HCC cell lines, HepG2 and PLC/PRF/5, by studying cell cycle regulatory proteins, and the MAP kinase and PDK1‐PKB/AKT signaling pathways. Etodolac inhibited growth and PCNA expression and induced cell cycle arrest in both HCC cell lines. Etodolac induced p21 WAF1/Cip1 and p27 Kip1 expression and inhibited CDK2, CDK4, CDC2, cyclin A and cyclin B1 expression, but did not affect cyclin D1 or cyclin E. HGF and 10% FBS induced ERK phosphorylation, but phosphorylation of p38, JNK and AKT was down‐regulated by etodolac. PD98059, a selective inhibitor of ERK phosphorylation, induced growth inhibition, the expression of p27 Kip1 and cell cycle arrest. In conclusion, p21 WAF1/Cip1 p27 Kip1 , CDK2, CDK4, CDC2, cyclin A, cyclin B1 and the MAP kinase signaling pathway are involved in growth inhibition and cell cycle arrest by a selective COX‐2 inhibitor in HCC cell lines.