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
- 1 December 1999
- journal article
- Published by Wiley in Japanese Journal of Cancer Research
- Vol. 90 (12) , 1364-1372
- https://doi.org/10.1111/j.1349-7006.1999.tb00721.x
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/WAF1and p27kipl. 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–phosphor‐ylated form of CDK2 protein, and coincided in part with up‐regulation of p27Kip1, but it was independent of the level of the p21Cip1/WAF1protein. 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.Keywords
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