Small-molecule RETRA suppresses mutant p53-bearing cancer cells through a p73-dependent salvage pathway
Open Access
- 29 April 2008
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 105 (17), 6302-6307
- https://doi.org/10.1073/pnas.0802091105
Abstract
Identification of unique features of cancer cells is important for defining specific and efficient therapeutic targets. Mutant p53 is present in nearly half of all cancer cases, forming a promising target for pharmacological reactivation. In addition to being defective for the tumor-suppressor function, mutant p53 contributes to malignancy by blocking a p53 family member p73. Here, we describe a small-molecule RETRA that activates a set of p53-regulated genes and specifically suppresses mutant p53-bearing tumor cells in vitro and in mouse xenografts. Although the effect is strictly limited to the cells expressing mutant p53, it is abrogated by inhibition with RNAi to p73. Treatment of mutant p53-expressing cancer cells with RETRA results in a substantial increase in the expression level of p73, and a release of p73 from the blocking complex with mutant p53, which produces tumor-suppressor effects similar to the functional reactivation of p53. RETRA is active against tumor cells expressing a variety of p53 mutants and does not affect normal cells. The results validate the mutant p53–p73 complex as a promising and highly specific potential target for cancer therapy.Keywords
This publication has 22 references indexed in Scilit:
- p73: A chiaroscuro gene in cancerEuropean Journal Of Cancer, 2007
- A p53-derived apoptotic peptide derepresses p73 to cause tumor regression in vivoJCI Insight, 2007
- Are interactions with p63 and p73 involved in mutant p53 gain of oncogenic function?Oncogene, 2007
- SHP-2 tyrosine phosphatase inhibits p73-dependent apoptosis and expression of a subset of p53 target genes induced by EGCGProceedings of the National Academy of Sciences, 2007
- ASPP: a new family of oncogenes and tumour suppressor genesBritish Journal of Cancer, 2007
- One, two, three—p53, p63, p73 and chemosensitivityDrug Resistance Updates, 2006
- Regulating p73 isoforms in human tumoursThe Journal of Pathology, 2006
- Small-molecule modulators of p53 family signaling and antitumor effects in p53-deficient human colon tumor xenograftsProceedings of the National Academy of Sciences, 2006
- Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compoundNature Medicine, 2002
- A Subset of Tumor-Derived Mutant Forms of p53 Down-Regulate p63 and p73 through a Direct Interaction with the p53 Core DomainMolecular and Cellular Biology, 2001