期刊
ONCOGENE
卷 29, 期 9, 页码 1329-1338出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2009.425
关键词
cancer; mutant p53; apoptosis; novel therapy
资金
- Swedish Cancer Society (Cancerfonden)
- Cancerforeningen
- Karolinska Institutet
- EU
The low molecular weight compound PRIMA-1(MET) reactivates mutant p53 and triggers mutant p53-dependent apoptosis in human tumor cells. We investigated the effect of PRIMA-1(MET) on global gene expression using microarray analysis of Saos-2 cells expressing His273 mutant p53 and parental p53 null Saos-2 cells. PRIMA-1(MET) 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-1(MET) in a mutant p53-dependent manner include the cell-cycle regulators GADD45B and 14-3-3 gamma 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-1(MET) 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-1(MET). Oncogene (2010) 29, 1329-1338; doi:10.1038/onc.2009.425; published online 30 November 2009
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