Involvement of p21 in mitotic exit after paclitaxel treatment in MCF-7 breast adenocarcinoma cell line.
It has been shown recently that expression of p21 is enhanced by paclitaxel. This cytotoxic compound induces mitotic spindle damage resulting in blockade of the mitotic cell cycle associated or not with apoptotic cell death. In the present study, we showed that, in MCF-7 cells, paclitaxel induced accumulation of p21 in cells with a G2/M DNA content, corresponding to cells either in abnormal mitosis or in an interphase-like state (decondensed chromatin) with multiple nuclei. In MCF-7 cells, the increase in p21 was subsequent to the mitotic arrest and was associated with the exit from abnormal mitosis leading to formation of cells with micronuclei. In this cell line, we noted a relationship between the elevation of p21 expression and the inhibition of p34cdc2 activity. High levels of p21 protein were also found to be associated with inactive p34cdc2/cyclin B protein complex after treatment with paclitaxel. Treatment with p21 antisense oligonucleotide partially blocked induction of p21 expression by paclitaxel and significantly reduced survival of MCF-7 cells exposed to this agent. In NIH-OVCAR-3 cells, which are deficient in basal and paclitaxel-induced p21 expression, paclitaxel led to a prolonged activation of p34cdc2 and a delayed mitotic exit associated with apoptotic cell death. These observations suggest that p21 is not required for the mitotic arrest in response to paclitaxel, but argue in favor of a role for this inhibitor in facilitating the exit from abnormal mitosis. This effectively enhances cell survival after paclitaxel-induced spindle damage.
Barboule
N
N
IPBS, CNRS 205, Toulouse, France.
Chadebech
P
P
Baldin
V
V
Vidal
S
S
Valette
A
A
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D016203:CDC2 Protein Kinase / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005260:Female; D006801:Humans; D008938:Mitosis / Q000187:drug effects*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010051:Ovarian Neoplasms; D017239:Paclitaxel / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016376:Oligonucleotides, Antisense; D016203:CDC2 Protein Kinase; D017239:Paclitaxel