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

Overview

Journal Cancer Res

Specialty Oncology

Date 2008 Oct 17

PMID 18922897

Citations 40

Authors

Hong Shen

Diarmuid M Moran

Carl G Maki

Affiliations

Soon will be listed here.

Abstract

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 G(1) and G(2) 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

Citing Articles

Determinants of Aurora kinase B inhibitor sensitivity in small cell lung cancer.

Duan L, Maki C Transl Lung Cancer Res. 2024; 13(2):223-228.

PMID: 38496702 PMC: 10938090. DOI: 10.21037/tlcr-23-732.

What Are the Reasons for Continuing Failures in Cancer Therapy? Are Misleading/Inappropriate Preclinical Assays to Be Blamed? Might Some Modern Therapies Cause More Harm than Benefit?.

Mirzayans R, Murray D Int J Mol Sci. 2022; 23(21).

PMID: 36362004 PMC: 9655591. DOI: 10.3390/ijms232113217.

p52-ZER6: a determinant of tumor cell sensitivity to MDM2-p53 binding inhibitors.

Li W, Alfason L, Huang C, Tang Y, Qiu L, Miyagishi M Acta Pharmacol Sin. 2022; 44(3):647-660.

PMID: 35995868 PMC: 9958181. DOI: 10.1038/s41401-022-00973-9.

Resistance mechanisms to inhibitors of p53-MDM2 interactions in cancer therapy: can we overcome them?.

Haronikova L, Bonczek O, Zatloukalova P, Kokas-Zavadil F, Kucerikova M, Coates P Cell Mol Biol Lett. 2021; 26(1):53.

PMID: 34911439 PMC: 8903693. DOI: 10.1186/s11658-021-00293-6.

Persistent DNA damage signaling and DNA polymerase theta promote broken chromosome segregation.

Clay D, Bretscher H, Jezuit E, Bush K, Fox D J Cell Biol. 2021; 220(12).

PMID: 34613334 PMC: 8500225. DOI: 10.1083/jcb.202106116.

References

Schwartz J, Murnane J, Weichselbaum R . The contribution of DNA ploidy to radiation sensitivity in human tumour cell lines. Br J Cancer. 1999; 79(5-6):744-7. PMC: 2362676. DOI: 10.1038/sj.bjc.6690119. View

Hendrickson M, Madine M, Dalton S, Gautier J . Phosphorylation of MCM4 by cdc2 protein kinase inhibits the activity of the minichromosome maintenance complex. Proc Natl Acad Sci U S A. 1996; 93(22):12223-8. PMC: 37971. DOI: 10.1073/pnas.93.22.12223. View

Galipeau P, Cowan D, Sanchez C, Barrett M, Emond M, Levine D . 17p (p53) allelic losses, 4N (G2/tetraploid) populations, and progression to aneuploidy in Barrett's esophagus. Proc Natl Acad Sci U S A. 1996; 93(14):7081-4. PMC: 38939. DOI: 10.1073/pnas.93.14.7081. View

Ganem N, Pellman D . Limiting the proliferation of polyploid cells. Cell. 2007; 131(3):437-40. DOI: 10.1016/j.cell.2007.10.024. View

Stewart Z, Leach S, Pietenpol J . p21(Waf1/Cip1) inhibition of cyclin E/Cdk2 activity prevents endoreduplication after mitotic spindle disruption. Mol Cell Biol. 1998; 19(1):205-15. PMC: 83879. DOI: 10.1128/MCB.19.1.205. View

Nguyen V, Co C, Li J . Cyclin-dependent kinases prevent DNA re-replication through multiple mechanisms. Nature. 2001; 411(6841):1068-73. DOI: 10.1038/35082600. View

Khan S, Wahl G . p53 and pRb prevent rereplication in response to microtubule inhibitors by mediating a reversible G1 arrest. Cancer Res. 1998; 58(3):396-401. View

Badie C, Itzhaki J, Sullivan M, Carpenter A, Porter A . Repression of CDK1 and other genes with CDE and CHR promoter elements during DNA damage-induced G(2)/M arrest in human cells. Mol Cell Biol. 2000; 20(7):2358-66. PMC: 85407. DOI: 10.1128/MCB.20.7.2358-2366.2000. View

Fujita M, Yamada C, Tsurumi T, Hanaoka F, Matsuzawa K, Inagaki M . Cell cycle- and chromatin binding state-dependent phosphorylation of human MCM heterohexameric complexes. A role for cdc2 kinase. J Biol Chem. 1998; 273(27):17095-101. DOI: 10.1074/jbc.273.27.17095. View

10.

de Toledo S, Azzam E, Keng P, Laffrenier S, Little J . Regulation by ionizing radiation of CDC2, cyclin A, cyclin B, thymidine kinase, topoisomerase IIalpha, and RAD51 expression in normal human diploid fibroblasts is dependent on p53/p21Waf1. Cell Growth Differ. 1998; 9(11):887-96. View

11.

Fujita M . Cdt1 revisited: complex and tight regulation during the cell cycle and consequences of deregulation in mammalian cells. Cell Div. 2006; 1:22. PMC: 1621056. DOI: 10.1186/1747-1028-1-22. View

12.

Di Leonardo A, Khan S, Linke S, Greco V, Seidita G, Wahl G . DNA rereplication in the presence of mitotic spindle inhibitors in human and mouse fibroblasts lacking either p53 or pRb function. Cancer Res. 1997; 57(6):1013-9. View

13.

Kubbutat M, Jones S, Vousden K . Regulation of p53 stability by Mdm2. Nature. 1997; 387(6630):299-303. DOI: 10.1038/387299a0. View

14.

Bunz F, Dutriaux A, Lengauer C, Waldman T, Zhou S, Brown J . Requirement for p53 and p21 to sustain G2 arrest after DNA damage. Science. 1998; 282(5393):1497-501. DOI: 10.1126/science.282.5393.1497. View

15.

Vousden K, Lu X . Live or let die: the cell's response to p53. Nat Rev Cancer. 2002; 2(8):594-604. DOI: 10.1038/nrc864. View

16.

Jiang W, Wells N, Hunter T . Multistep regulation of DNA replication by Cdk phosphorylation of HsCdc6. Proc Natl Acad Sci U S A. 1999; 96(11):6193-8. PMC: 26858. DOI: 10.1073/pnas.96.11.6193. View

17.

Coll-Mulet L, Iglesias-Serret D, Santidrian A, Cosialls A, de Frias M, Castano E . MDM2 antagonists activate p53 and synergize with genotoxic drugs in B-cell chronic lymphocytic leukemia cells. Blood. 2006; 107(10):4109-14. DOI: 10.1182/blood-2005-08-3273. View

18.

Mihaylov I, Kondo T, Jones L, Ryzhikov S, Tanaka J, Zheng J . Control of DNA replication and chromosome ploidy by geminin and cyclin A. Mol Cell Biol. 2002; 22(6):1868-80. PMC: 135598. DOI: 10.1128/MCB.22.6.1868-1880.2002. View

19.

Haupt Y, Maya R, Kazaz A, Oren M . Mdm2 promotes the rapid degradation of p53. Nature. 1997; 387(6630):296-9. DOI: 10.1038/387296a0. View

20.

Kranz D, Dobbelstein M . Nongenotoxic p53 activation protects cells against S-phase-specific chemotherapy. Cancer Res. 2006; 66(21):10274-80. DOI: 10.1158/0008-5472.CAN-06-1527. View