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
T. Akiyama et al., 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, JPN J CANC, 90(12), 1999, pp. 1364-1372
7-Hydroxystaurosporine (UCN-01), which was originally identified as a prote
in kinase C selective inhibitor, is currently in clinical trials as an anti
-cancer drug. We previously showed that UCN-01 induced preferential G1-phas
e accumulation in tumor cells and this effect was associated with the retin
oblastoma (Rb) protein and its regulatory factors, such as cyclin-dependent
kinase 2 (CDK2) and CDK inhibitors p21(Cip1/WAF1) and p27(Kip1). We demons
trate here that G1-phase accumulation was induced by UCN-01 in Rb-proficien
t cell lines (WiDr and HCT116 human colon carcinomas and WI-38 human Lung f
ibroblast), and it was accompanied by dephosphorylation of Rb. in addition,
UCN-01-induced G1-phase accumulation was also demonstrated in a Rb-defecti
ve cell line (Saos-2 human osteosarcoma), but not in a simian virus 40 (SV4
0)-transformed cell line (WI-38 VA13). Apoptosis was induced by UCN-01 in t
he two Rb-deficient cell lines, but not in the other Rh-proficient cell lin
es. These observations suggest that G1-checkpoint function might be importa
nt for cell survival during UCN-01 treatment. In addition, there may be a U
CN-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 activit
y. This reduction was strictly dependent on down-regulation of the Thr160-p
hosphorylated form of CDK2 protein, and coincided in part with up-regulatio
n of p27(Kip1), but it was independent of the level of the p21(Cip1/WAF1) p
rotein. 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.