Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis.
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).
Lambert
J M R
JM
Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden.
Moshfegh
A
A
Hainaut
P
P
Wiman
K G
KG
Bykov
V J N
VJ
D017209:Apoptosis / Q000502:physiology*; D016158:Genes, p53 / Q000502:physiology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000494:pharmacology*
D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C446290:PRIMA1 protein, human; D016159:Tumor Suppressor Protein p53