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Carcinogenesis Advance Access published online on November 28, 2007
Carcinogenesis, doi:10.1093/carcin/bgm266
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Published by Oxford University Press 2007.
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org

In vitro and in vivo cytotoxic effects of PRIMA-1 on Hepatocellular Carcinoma cells expressing mutant p53ser249

Hong Shi1, Jeremy Lambert1,2, Agnes Hautefeuille1, Vladimir Bykov2, Klas Wiman2, Pierre Hainaut1,* and Claude Caron de Fromentel3

1 International Agency for Research on Cancer, 150 cours Albert Thomas, 69372 Lyon Cedex 08, France
2 Karolinska Institutet, Department of Oncology-Pathology, Cancer Center Karolinska
(CCK), Karolinska University Hospital, 171 77 Stockholm, Sweden
3 Unité INSERM U590, Université Lyon-1, Centre Léon Bérard, 28 rue Laennec, 69373 Lyon Cedex 08, France

* Corresponding author: Pierre Hainaut: telephone: 33 472738532; fax: 33 472738322; e-mail: hainaut{at}iarc.fr

Hepatocellular carcinoma (HCC) is highly lethal due to limited curative options. In high-incidence regions, such as parts of Africa and South-Eastern Asia, over 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 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 (SCID) 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, 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.

Key Words: PRIMA-1 • HCC cell lines • Mutant p53 • p53ser249

Received June 15, 2007; revised November 15, 2007; accepted November 18, 2007.


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