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

• Published in: Carcinogenesis (New York) Vol. 29; no. 7; pp. 1428 - 1434
• Main Authors: Shi, Hong, Lambert, Jeremy M.R., Hautefeuille, Agnes, Bykov, Vladimir J.N., Wiman, Klas G., Hainaut, Pierre, de Fromentel, Claude Caron
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.07.2008; Oxford Publishing Limited (England)
• Subjects: Animals; Apoptosis - drug effects; Apoptosis - genetics; Aza Compounds - pharmacology; Biological and medical sciences; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Carcinogenesis, carcinogens and anticarcinogens; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Cell Line, Tumor; Cell Nucleolus - metabolism; DNA, Neoplasm - genetics; DNA, Neoplasm - metabolism; Gastroenterology. Liver. Pancreas. Abdomen; Gene Silencing; Humans; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical sciences; Medicin och hälsovetenskap; Mice; Mice, SCID; Mutation; RNA, Small Interfering - genetics; Transcriptional Activation - drug effects; Transfection; Tumor Suppressor Protein p53 - biosynthesis; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumors; Xenograft Model Antitumor Assays; Liver cancer; In vivo; Digestive diseases; Hepatic disease; Hepatocellular carcinoma; Cytotoxicity; Malignant tumor; Mutation; In vitro; Cancer
• ISSN: 0143-3334; 1460-2180; 1460-2180
• DOI: 10.1093/carcin/bgm266

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.