p21Cip1, regulator of fine-tuned mitosis and anti-cancer target

• Published in: Geburtshilfe und Frauenheilkunde
• Main Authors: Kreis, NN, Zimmer, B, Rieger, MA, Louwen, F, Yuan, J
• Format: Conference Proceeding
• Language: English
• Published: 05.09.2014
• ISSN: 0016-5751; 1438-8804
• DOI: 10.1055/s-0034-1388421

Deregulated cell cycle is a hallmark of tumor development. p21 Cip1 is a key player in regulating the cell cycle and has been shown to be a tumor suppressor and an oncogene as well. Its function in the interphase of the cell cycle is well studied and its potential role in mitosis is only anticipated. We show that p21 Cip1 is important for a fine-tuned mitotic progression by inhibiting the activity of cyclin-dependent kinase 1 (Cdk1)/cyclin B1, the master kinase of mitosis. Loss of p21 Cip1 prolongs the duration of mitosis by arresting cells at metaphase, anaphase and cytokinesis. Time-lapse microscopy experiments and immunofluorescence staining revealed that p21 Cip1 is critical for proper chromosome segregation and cytokinesis in tumor cells promoting genomic stability. Moreover, p21 Cip1 is responsible for susceptibility to many mitotic anti-cancer drugs, such as paclitaxel and mitotic kinase inhibitors. We have studied the impact of p21 Cip1 on efficacy of Poloxin, a small-molecule inhibitor targeting Polo-like kinase 1 (Plk1), a critical mitotic kinase and deregulated in various cancer entities. Our data suggest that deficiency of p21 makes tumor cells susceptible to Poloxin. Intriguingly, upon treatment with Poloxin, p21 Cip1 is increased and localized in the cytoplasm, which blocks the induction of apoptosis, possibly associated with therapy resistance. Further investigations are required to reveal the underlying molecular mechanisms and to define in which cellular context p21 Cip1 could be considered as a candidate for anticancer therapy.