RRC ID 39429
著者 Akiyama T, Sugiyama K, Shimizu M, Tamaoki T, Akinaga S.
タイトル G1-checkpoint function including a cyclin-dependent kinase 2 regulatory pathway as potential determinant of 7-hydroxystaurosporine (UCN-01)-induced apoptosis and G1-phase accumulation.
ジャーナル Jpn J Cancer Res
Abstract 7-Hydroxystaurosporine (UCN-01), which was originally identified as a protein kinase C selective inhibitor, is currently in clinical trials as an anti-cancer drug. We previously showed that UCN-01 induced preferential G1-phase accumulation in tumor cells and this effect was associated with the retinoblastoma (Rb) protein and its regulatory factors, such as cyclin-dependent kinase 2 (CDK2) and CDK inhibitors p21Cip1/WAF1 and p27Kip1. We demonstrate here that G1-phase accumulation was induced by UCN-01 in Rb-proficient cell lines (WiDr and HCT116 human colon carcinomas and WI-38 human lung fibroblast), and it was accompanied by dephosphorylation of Rb. In addition, UCN-01-induced G1-phase accumulation was also demonstrated in a Rb-defective cell line (Saos-2 human osteosarcoma), but not in a simian virus 40 (SV40)-transformed cell line (WI-38 VA13). Apoptosis was induced by UCN-01 in the two Rb-deficient cell lines, but not in the other Rb-proficient cell lines. These observations suggest that G1-checkpoint function might be important for cell survival during UCN-01 treatment. In addition, there may be a UCN-01-responsive factor in the G1-checkpoint machinery other than Rb which is targeted by SV40. Further studies revealed a correlation between UCN-01-induced G1-phase accumulation and reduction of cellular CDK2 kinase activity. This reduction was strictly dependent on down-regulation of the Thr160-phosphorylated form of CDK2 protein, and coincided in part with up-regulation of p27Kip1, but it was independent of the level of the p21Cip1/WAF1 protein. These results suggest that G1-checkpoint function, including a CDK2-regulatory pathway, may be a significant determinant of the sensitivity of tumor cells to UCN-01.
巻・号 90(12)
ページ 1364-72
公開日 1999-12-1
DOI 10.1111/j.1349-7006.1999.tb00721.x
PII S091050500087091X
PMID 10665655
PMC PMC5926038
MeSH Alkaloids / pharmacology* Antineoplastic Agents / pharmacology* Apoptosis / drug effects* CDC2-CDC28 Kinases* Cell Cycle / drug effects Cell Cycle Proteins / metabolism Cell Cycle Proteins / physiology Cell Line, Transformed Cyclin-Dependent Kinase 2 Cyclin-Dependent Kinase Inhibitor p21 Cyclin-Dependent Kinase Inhibitor p27 Cyclin-Dependent Kinases / antagonists & inhibitors Cyclin-Dependent Kinases / biosynthesis Cyclin-Dependent Kinases / metabolism Cyclin-Dependent Kinases / physiology* Cyclins / biosynthesis Cyclins / physiology Enzyme Inhibitors / pharmacology G1 Phase / drug effects* Growth Inhibitors / pharmacology Humans Microtubule-Associated Proteins / biosynthesis Microtubule-Associated Proteins / physiology Phosphorylation Protein Serine-Threonine Kinases / antagonists & inhibitors Protein Serine-Threonine Kinases / biosynthesis Protein Serine-Threonine Kinases / metabolism Protein Serine-Threonine Kinases / physiology* Retinoblastoma Protein / metabolism Signal Transduction / drug effects* Staurosporine / analogs & derivatives Tumor Cells, Cultured Tumor Suppressor Proteins*
引用数 22
WOS 分野 ONCOLOGY
リソース情報
ヒト・動物細胞 WI-38