期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 105, 期 17, 页码 6302-6307出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0802091105
关键词
cancer therapy; p73 family; tumor suppressors
资金
- Howard Hughes Medical Institute [55005603] Funding Source: Medline
- NCI NIH HHS [R01CA10490, R01 CA104903-05, R01CA075179, R01 CA075179, R01 CA104903] Funding Source: Medline
- NIA NIH HHS [R01AG025278, R01 AG025278-04, R01 AG025278] Funding Source: Medline
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.
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