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

Pharmacological reactivation of mutant p53: from protein structure to the cancer patient

“…We found that PRIMA-1 and APR-246 induce activation of caspase-2, caspase-3 and caspase-9, consistent with induction of apoptosis via the mitochondrial pathway (Shen et al, 2008). Moreover, microarray analysis revealed that APR-246 induces a limited set of genes in a mutant p53-dependent manner, followed by ER stress (Lambert et al, 2010; Figure 3). Yet the question remained as to how these compounds affect mutant p53.…”

“…PRIMA-1 also activates caspase-2, followed by activation of caspase-3 and caspase-9. This triggers cell death by apoptosis (Shen et al, 2008;Lambert et al, 2010).…”

PRIMA-1MET/APR-246 targets mutant forms of p53 family members p63 and p73

“…In contrast, PRIMA-1 MET induced apoptosis in cells expressing ts TAp63g and TAp73b but not in ts TAp73a-expressing cells, suggesting that temperature shift and PRIMA-1 MET treatment act differently with respect to restoring wild-type function to mutant p73. It is conceivable that adducts of the PRIMA-1 MET conversion product MQ could create novel protein-DNA contacts (Lambert et al, 2009(Lambert et al, , 2010. This could affect the choice of target genes and thus result in a different biological outcome than reactivation by temperature shift.…”

“…We will henceforth refer to it as PRIMA-1 MET . PRIMA-1 MET induces mutant p53-dependent apoptosis via multiple signaling pathways including upregulation of mitochondrial p53 target proteins such as Bax, Puma, and Noxa, activation of caspase-2, and ER stress (Shen et al, 2008;Lambert et al, 2010). PRIMA-1 has also been shown to trigger mutant p53-mediated transcription-independent apoptosis (Chipuk et al, 2003).…”

Pharmacological activation of p53 triggers anticancer innate immune response through induction of ULBP2

“…We analyzed publicly available microarray data on p53 response in isogenic lines, p53-His273-expressing Saos2 cells and p53-null Saos2 cells, after activation by PRIMA-1 MET /Apr-246, a molecule currently being tested in a clinical trial to restore wild-type properties to mutant p53 in patients. [23][24][25] We found significant p53-dependent induction of ULBP2 transcription, as the induction of ULBP2 transcription by PRIMA-1 MET /Apr-246 was only detected in p53-His273-expressing Saos2 cells but not in p53-null Saos2 cells. We also found the induction of ULBP2 among 569 differently expressed genes upon p53 activation by another p53 activator, actinomycin D, in p53-positive but not p53-null HCT116 cells, as assessed by microarray analysis.…”