In vitro and in vivo cytotoxic effects of PRIMA-1 on hepatocellular carcinoma cells expressing mutant p53ser249.

Abstract

Hepatocellular carcinoma (HCC) is highly lethal due to limited curative options. In high-incidence regions, such as parts of Africa and Southeastern Asia, >50% of cases carry an AGG to AGT mutation at codon 249 of the TP53 gene, considered as a 'signature' of mutagenesis by aflatoxins. The protein product, p53ser249, may represent a therapeutic target for HCC. The small molecule p53 reactivation and induction of massive apoptosis (PRIMA)-1 has been shown to induce apoptosis in tumour cells by reactivating the transactivation capacity of some p53 mutants. In this study, we have investigated the cytotoxic effects of PRIMA-1 on HCC cells expressing p53ser249. In p53-null Hep3B cells, over-expression of p53ser249 or p53gln248 by stable transfection increased the cytotoxicity of PRIMA-1 at 50 muM. Furthermore, PRIMA-1 treatment delayed the growth of p53ser249-expressing Hep3B cells xenografted in severe combined immunodeficiency mice. However, PRIMA-1 did not restore wild-type DNA binding and transactivation activities to p53ser249 or to p53gln248 in Hep3B cells. Moreover, in PLC/PRF/5, a HCC cell line constitutively expressing p53ser249, small interfering RNA (siRNA) silencing of the mutant increased the cytotoxic effect of PRIMA-1. These apparently contradictory effects can be reconciled by proposing that p53ser249 exerts a gain-of-function effect, which favours the survival of HCC cells. Thus, both inhibition of this effect by PRIMA-1 and removal of the mutant by siRNA can lead to the decrease of survival capacity of HCC cells.

• Authors: Hong Shi, Jeremy M R Lambert, Agnes Hautefeuille, Vladimir J N Bykov, Klas G Wiman, Pierre Hainaut, Claude Caron de Fromentel
• Journal: Carcinogenesis (Carcinogenesis) Vol. 29 Issue 7 Pg. 1428-34 (Jul 2008) ISSN: 1460-2180 [Electronic] England
• PMID: 18048389 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aza Compounds
• Bridged Bicyclo Compounds, Heterocyclic
• DNA, Neoplasm
• RNA, Small Interfering
• Tumor Suppressor Protein p53
• 2,2-bis(hydroxymethyl)-1-azabicyclo(2,2,2,)octan-3-one

Topics

• Animals
• Apoptosis (drug effects, genetics)
• Aza Compounds (pharmacology)
• Bridged Bicyclo Compounds, Heterocyclic (pharmacology)
• Carcinoma, Hepatocellular (drug therapy, genetics, metabolism)
• Cell Line, Tumor
• Cell Nucleolus (metabolism)
• DNA, Neoplasm (genetics, metabolism)
• Gene Silencing
• Humans
• Liver Neoplasms (drug therapy, genetics, metabolism)
• Mice
• Mice, SCID
• Mutation
• RNA, Small Interfering (genetics)
• Transcriptional Activation (drug effects)
• Transfection
• Tumor Suppressor Protein p53 (biosynthesis, genetics, metabolism)
• Xenograft Model Antitumor Assays