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Troglitazone induces p27 Kip1 ‐associated cell‐cycle arrest through down‐regulating Skp2 in human hepatoma cells
Author(s) -
Koga Hironori,
Harada Masaru,
Ohtsubo Motoaki,
Shishido Shoichiro,
Kumemura Hiroto,
Hanada Shinichiro,
Taniguchi Eitaro,
Yamashita Katsumi,
Kumashiro Ryukichi,
Ueno Takato,
Sata Michio
Publication year - 2003
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1053/jhep.2003.50186
Subject(s) - troglitazone , skp2 , cancer research , cell cycle , transfection , biology , cancer cell , chemistry , cell , peroxisome proliferator activated receptor , microbiology and biotechnology , cell culture , receptor , ubiquitin ligase , cancer , ubiquitin , biochemistry , gene , genetics
Increasing evidence has confirmed that ligands for peroxisome proliferator‐activated receptor γ (PPARγ) exhibit antitumoral effects through inhibition of cell proliferation and induction of cell differentiation in several malignant neoplasms. Recently, we have documented the accumulation of a cyclin‐dependent kinase inhibitor, p27 Kip1 , as well as an unexpected accumulation in cyclin E in G1‐arrested human hepatoma cells treated with the PPARγ ligand troglitazone. Simultaneous accumulations in both p27 Kip1 and cyclin E are known to be characteristic phenotypes in cells derived from mice lacking Skp2, an F‐box protein component of the SCF ubiquitin‐ligase complex. Thus, the aim of the present study was to assess whether Skp2 might be involved in the down‐regulation of p27 Kip1 in troglitazone‐treated human hepatoma cells. A striking decrease in Skp2 expression and a reciprocal increase in p27 Kip1 expression were found in troglitazone‐treated hepatoma cells but not in those cells treated with other PPARγ ligands such as pioglitazone and ciglitazone. Quantitative real‐time RT‐PCR analysis showed that troglitazone down‐regulated Skp2 at the mRNA levels. Consistently, ectopic overexpression in Skp2 brought resistance to troglitazone, resulting in a decreased population of arrested cells at the G1 phase compared with that in the mock‐transfected cells. In surgically resected hepatocellular carcinoma (HCC) tissue, an increased expression in Skp2 was found in both the moderately differentiated HCCs and the poorly differentiated HCCs. In conclusion, troglitazone attenuated Skp2 expression, thereby promoting p27 Kip1 accumulation in human hepatoma cells. This therapeutic potential of the ligand may lead to new cell‐cycle‐based antitumor strategies for advanced HCCs.