Small-molecule RETRA suppresses mutant p53-bearing cancer cells through a p73-dependent salvage pathway
| Autor: | D. V. Kochetkov, Evguenia Strom, Julia E. Kravchenko, Andrei V. Gudkov, Elena I. Frolova, Elena Feinstein, P. M. Chumakov, I. Kovriga, Pavel G. Komarov, G. V. Ilyinskaya, L. S. Agapova |
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| Rok vydání: | 2008 |
| Předmět: |
Transcription
Genetic Mutant Catechols Antineoplastic Agents Biology DNA-binding protein Small Molecule Libraries Mice RNA interference Genes Reporter Cell Line Tumor Neoplasms Animals Humans RNA Messenger Nuclear protein Regulation of gene expression Multidisciplinary Tumor Suppressor Proteins Nuclear Proteins Biological Sciences Molecular biology In vitro Cell biology Neoplasm Proteins DNA-Binding Proteins Gene Expression Regulation Neoplastic Thiazoles Cell culture Cancer cell Mutant Proteins Drug Screening Assays Antitumor Tumor Suppressor Protein p53 |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America. 105(17) |
| ISSN: | 1091-6490 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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