Persistent p21 expression after Nutlin-3a removal is associated with senescence-like arrest in 4N cells.

Abstract

Nutlin-3a is a preclinical drug that stabilizes p53 by blocking the interaction between p53 and MDM2. In our previous study, Nutlin-3a promoted a tetraploid G(1) arrest in two p53 wild-type cell lines (HCT116 and U2OS), and both cell lines underwent endoreduplication after Nutlin-3a removal. Endoreduplication gave rise to stable tetraploid clones resistant to therapy-induced apoptosis. Prior knowledge of whether cells are susceptible to Nutlin-induced endoreduplication and therapy resistance could help direct Nutlin-3a-based therapies. In the present study, Nutlin-3a promoted a tetraploid G(1) arrest in multiple p53 wild-type cell lines. However, some cell lines underwent endoreduplication to relatively high extents after Nutlin-3a removal whereas other cell lines did not. The resistance to endoreduplication observed in some cell lines was associated with a prolonged 4N arrest after Nutlin-3a removal. Knockdown of either p53 or p21 immediately after Nutlin-3a removal could drive endoreduplication in otherwise resistant 4N cells. Finally, 4N-arrested cells retained persistent p21 expression; expressed senescence-associated beta-galactosidase; displayed an enlarged, flattened phenotype; and underwent a proliferation block that lasted at least 2 weeks after Nutlin-3a removal. These findings demonstrate that transient Nutlin-3a treatment can promote an apparently permanent proliferative block in 4N cells of certain cell lines associated with persistent p21 expression and resistance to endoreduplication.

• Authors: Hong Shen, Carl G Maki
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 285 Issue 30 Pg. 23105-14 (Jul 23 2010) ISSN: 1083-351X [Electronic] United States
• PMID: 20489208 (Publication Type: Journal Article)

Chemical References

• Cyclin-Dependent Kinase Inhibitor p21
• Imidazoles
• Piperazines
• Tumor Suppressor Protein p53
• nutlin 3

Topics

• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cellular Senescence (drug effects)
• Cyclin-Dependent Kinase Inhibitor p21 (metabolism)
• G1 Phase (drug effects)
• Gene Expression Regulation (drug effects)
• Humans
• Imidazoles (pharmacology)
• Piperazines (pharmacology)
• Polyploidy
• Tumor Suppressor Protein p53 (metabolism)