Differential modulation of paclitaxel-mediated apoptosis by p21(Waf1) and p27(Kip1)

Abstract

The impact of the cyclin dependent kinase (CDK) inhibitors p21(Waf1) and p27(Kip1) on paclitaxel-mediated cytotoxicity was investigated in RKO human colon adenocarcinoma cells with the ecdysone-inducible expression of p21(Waf1) or p27(Kip1). Ectopic expression of p27(Kip1) arrested cells at G1 phase, whereas p21(Waf1) expression arrested cells at G1 and G2. Expression of p21(Waf1) after paclitaxel treatment produced much greater resistance to paclitaxel than did expression of p27(Kip1). We attributed this difference to the additional block at G2 induced by p21(Waf1), which presented cells from entering M phase and becoming paclitaxel susceptible. Expression of p21(Waf1) inhibited p34cdc2 activity and markedly reduced paclitaxel-mediated mitotic arrest, from 87.5 to 23%. In contrast, p27(Kip1) expression also inhibited p34cdc2 but reduced mitotic arrest only slightly, from 87.4 to 74.5%. We concluded that the G2 block produced by p21(Waf1), but not by p27(Kip1), contributed to their unequal modulation of sensitivity to paclitaxel-mediated apoptosis in RKO cells, and there is no causal relationship between paclitaxel-mediated cytotoxicity and elevation of p34cdc2 activity.