Transient nutlin-3a treatment promotes endoreduplication and the generation of therapy-resistant tetraploid cells.
Transient nutlin-3a treatment promotes endoreduplication and the generation of therapy-resistant tetraploid cells.
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DOI：
10.1158/0008-5472.can-08-1901
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发表时间：
2008-10-15
期刊：
影响因子：
11.2
通讯作者：
Maki CG
中科院分区：
文献类型：
--
作者：
Shen H;Moran DM;Maki CG
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 hrs accumulated with 2N and 4N DNA content, suggestive of G1 and G2-phase cell cycle arrest. This coincided with increased p53 and p21 expression, hypo-phosphorylation 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 IR 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.
