Small-molecule RETRA suppresses mutant p53-bearing cancer cells through a p73-dependent salvage pathway

Proc Natl Acad Sci U S A. 2008 Apr 29;105(17):6302-7. doi: 10.1073/pnas.0802091105. Epub 2008 Apr 18.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Catechols / chemistry
  • Catechols / pharmacology*
  • Cell Line, Tumor
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Drug Screening Assays, Antitumor
  • Gene Expression Regulation, Neoplastic / drug effects
  • Genes, Reporter
  • Humans
  • Mice
  • Mutant Proteins / metabolism*
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Neoplasms / pathology*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Thiazoles / chemistry
  • Thiazoles / pharmacology*
  • Transcription, Genetic / drug effects
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*

Substances

  • 2-(4,5-dihydro-1,3-thiazol-2-ylthio)-1-(3,4-dihydroxyphenyl)ethanone
  • Antineoplastic Agents
  • Catechols
  • DNA-Binding Proteins
  • Mutant Proteins
  • Neoplasm Proteins
  • Nuclear Proteins
  • RNA, Messenger
  • Small Molecule Libraries
  • Thiazoles
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins