Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden.
Oncogene. 2010 Mar 4;29(9):1329-38. doi: 10.1038/onc.2009.425. Epub 2009 Nov 30.
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 14-3-3gamma 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).
低分子量化合物 PRIMA-1（MET）可使突变型 p53 重新激活，并在人肿瘤细胞中引发依赖于突变型 p53 的细胞凋亡。我们使用表达 His273 突变型 p53 的 Saos-2 细胞和具有野生型 p53 的 Saos-2 细胞进行微阵列分析，研究了 PRIMA-1（MET）对整体基因表达的影响。与 p53 缺失的细胞相比，PRIMA-1（MET）在表达突变型 p53 的细胞中影响了更多数量的基因转录。PRIMA-1（MET）以依赖于突变型 p53 的方式影响的基因包括细胞周期调节因子 GADD45B 和 14-3-3γ以及促凋亡基因 Noxa。受 PRIMA-1（MET）影响的几个基因是已知的 p53 靶基因和/或含有 p53 DNA 结合基序。我们还发现突变型 p53 依赖性细胞骨架破坏，以及 XBP1 基因的转录激活和其 mRNA 的切割，这是内质网应激的一个标志。我们的数据表明，PRIMA-1（MET）通过多种转录依赖和非依赖途径诱导细胞凋亡。这种导致细胞凋亡的多种途径的整体参与与恢复突变型 p53 的野生型特性一致，并且可能降低 PRIMA-1（MET）在临床应用中产生耐药性的风险。
