Journal Article

<i>In vitro</i> and <i>in vivo</i> cytotoxic effects of PRIMA-1 on hepatocellular carcinoma cells expressing mutant p53ser249

Hong Shi, Jeremy M.R. Lambert, Agnes Hautefeuille, Vladimir J.N. Bykov, Klas G. Wiman, Pierre Hainaut and Claude Caron de Fromentel

in Carcinogenesis

Volume 29, issue 7, pages 1428-1434
Published in print July 2008 | ISSN: 0143-3334
Published online November 2007 | e-ISSN: 1460-2180 | DOI:
In vitro and in vivo cytotoxic effects of PRIMA-1 on hepatocellular carcinoma cells expressing mutant p53ser249

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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 μM. 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.

Journal Article.  5796 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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