HIPK2 Regulation by MDM2 Determines Tumor Cell Response to the p53-Reactivating Drugs Nutlin-3 and RITA

In the past few years, much effort has been devoted to show the single-target specificity of nongenotoxic, p53 reactivating compounds. However, the divergent biological responses induced by the different compounds, even in the same tumor cells, demand additional mechanistic insights, whose knowledge...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2009-08, Vol.69 (15), p.6241-6248
Main Authors: RINALDO, Cinzia, PRODOSMO, Andrea, SIEPI, Francesca, MONCADA, Alice, SACCHI, Ada, SELIVANOVA, Galina, SODDU, Silvia
Format: Article
Language:English
Subjects:
Antineoplastic agents
Apoptosis - drug effects
Apoptosis - physiology
Biological and medical sciences
Carrier Proteins - biosynthesis
Carrier Proteins - genetics
Carrier Proteins - metabolism
Cell Line, Tumor
Furans - pharmacology
HCT116 Cells
Humans
Imidazoles - pharmacology
Medical sciences
Medicin och hälsovetenskap
Mitosis - drug effects
Pharmacology. Drug treatments
Piperazines - pharmacology
Protein-Serine-Threonine Kinases - biosynthesis
Protein-Serine-Threonine Kinases - deficiency
Protein-Serine-Threonine Kinases - genetics
Protein-Serine-Threonine Kinases - metabolism
Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors
Proto-Oncogene Proteins c-mdm2 - metabolism
RNA, Messenger - biosynthesis
RNA, Messenger - genetics
Tumor Suppressor Protein p53 - metabolism
Tumors
Up-Regulation - drug effects
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Summary:In the past few years, much effort has been devoted to show the single-target specificity of nongenotoxic, p53 reactivating compounds. However, the divergent biological responses induced by the different compounds, even in the same tumor cells, demand additional mechanistic insights, whose knowledge may lead to improved drug design or selection of the most potent drug combinations. To address the molecular mechanism underlying induction of mitotic arrest versus clinically more desirable apoptosis, we took advantage of two MDM2 antagonists, Nutlin-3 and RITA, which respectively produce these two outcomes. We show that, along with p53 reactivation, the proapoptotic p53-activator HIPK2 is degraded by MDM2 in Nutlin-3-treated cells, but activated by transiently reduced MDM2 levels in RITA-treated ones. Gain- and loss-of-function experiments revealed the functional significance of MDM2-mediated HIPK2 regulation in cell decision between mitotic arrest and apoptosis in both types of p53 reactivation. These data indicate that strategies of p53 reactivation by MDM2 inhibition should also take into consideration MDM2 targets other than p53, such as the apoptosis activator HIPK2.
ISSN:0008-5472
1538-7445
1538-7445
DOI:10.1158/0008-5472.CAN-09-0337