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Transient Nutlin-3a Treatment Promotes Endoreduplication and the Generation of Therapy-Resistant Tetraploid Cells

Department of Radiation Oncology, University of Chicago, Chicago, Illinois

Requests for reprints: Carl G. Maki, Department of Radiation Oncology, University of Chicago, 5841 South Maryland Avenue, MC1105, Room G-06, Chicago, IL 60637. Phone: 773-834-4391; Fax: 773-702-1968; E-mail: cmaki{at}rover.uchicago.edu.

Key Words: endoreduplication • Nutlin • p53

p53 activity is controlled in large part by MDM2, an E3 ubiquitin ligase that binds p53 and promotes its degradation. The MDM2 antagonist Nutlin-3a stabilizes p53 by blocking its interaction with MDM2. Several studies have supported the potential use of Nutlin-3a in cancer therapy. Two different p53 wild-type cancer cell lines (U2OS and HCT116) treated with Nutlin-3a for 24 hours accumulated 2N and 4N DNA content, suggestive of G₁ and G₂ phase cell cycle arrest. This coincided with increased p53 and p21 expression, hypophosphorylation of pRb, and depletion of Cyclin B1, Cyclin A, and CDC2. Upon removal of Nutlin-3a, 4N cells entered S phase and re-replicated their DNA without an intervening mitotic division, a process known as endoreduplication. p53-p21 pathway activation was required for the depletion of Cyclin B1, Cyclin A, and CDC2 in Nutlin-3a–treated cells and for endoreduplication after Nutlin-3a removal. Stable tetraploid clones could be isolated from Nutlin-3a treated cells, and these tetraploid clones were more resistant to ionizing radiation and cisplatin-induced apoptosis than diploid counterparts. These data indicate that transient Nutlin-3a treatment of p53 wild-type cancer cells can promote endoreduplication and the generation of therapy-resistant tetraploid cells. These findings have important implications regarding the use of Nutlin-3a in cancer therapy.[Cancer Res 2008;68(20):8260–8]

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