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Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis

Oncogene volume 29, pages 1329–1338 (2010)Cite this article

Abstract

The low molecular weight compound PRIMA-1MET reactivates mutant p53 and triggers mutant p53-dependent apoptosis in human tumor cells. We investigated the effect of PRIMA-1MET on global gene expression using microarray analysis of Saos-2 cells expressing His273 mutant p53 and parental p53 null Saos-2 cells. PRIMA-1MET affected transcription of a significantly larger number of genes in the mutant p53-expressing cells compared to the p53 null cells. Genes affected by PRIMA-1MET in a mutant p53-dependent manner include the cell-cycle regulators GADD45B and 14-3-3γ and the pro-apoptotic Noxa. Several of the affected genes are known p53 target genes and/or contain p53 DNA-binding motifs. We also found mutant p53-dependent disruption of the cytoskeleton, as well as transcriptional activation of the XBP1 gene and cleavage of its mRNA, a marker for endoplasmic reticulum stress. Our data show that PRIMA-1MET induces apoptosis through multiple transcription-dependent and -independent pathways. Such integral engagement of multiple pathways leading to apoptosis is consistent with restoration of wild-type properties to mutant p53 and is likely to reduce the risk of drug resistance development in clinical applications of PRIMA-1MET.

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Acknowledgements

We thank Bert Vogelstein, Johns Hopkins Oncology Center, for HCT116 cells. This work was supported by the Swedish Cancer Society (Cancerfonden), Cancerföreningen, Karolinska Institutet and the EU 6th framework program. This publication reflects the author's views and not necessarily those of the EC. The information in this document is provided as is and no guarantee or warranty is given that the information is fit for any particular purpose. The user thereof uses the information at his/her sole risk and liability. The Community is not liable for any use that may be made of the information contained herein.

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  1. Department of Oncology–Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden

    J M R Lambert, A Moshfegh, K G Wiman & V J N Bykov

  2. Molecular Carcinogenesis and Biomarkers Group, International Agency for Research on Cancer (IARC), Cours Albert Thomas, Lyon, France

    J M R Lambert & P Hainaut

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  1. J M R Lambert
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Correspondence to K G Wiman.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Lambert, J., Moshfegh, A., Hainaut, P. et al. Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene 29, 1329–1338 (2010). https://doi.org/10.1038/onc.2009.425

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