Targeting the p53 Family for Cancer Therapy: ‘Big Brother’ Joins the Fight

Abstract

Inactivation of p53-mediated signaling plays a major role in both the genesis and therapy resistance of human cancer. Nearly all tumors contain mutations in p53 itself or have perturbations in the p53 pathway. Since there is clear evidence that many tumor cells are more likely to die in response to wild-type p53 activation or restoration than are their normal counterparts, there has been considerable interest in the development of small molecules that target p53 for therapeutic gain. These include compounds that either revert mutant p53 back to its wild-type conformation or compounds which interfere with the binding to, or the ubiquitylation of, p53 by MDM2. In both cases, however, the efficacy of the strategy depends on the presence of either mutant or wild-type p53 respectively thereby limiting their application to specific tumor settings. As a result, recent strategies have turned to the p53 family member, p73, which like p53 is a potent inducer of death, but in contrast is rarely lost or mutated in tumors. We discuss here all these different strategies and in particular focus on the discovery of an apoptotic peptide which targets not just p73, but potentially all p53 family members to cause tumor cell death.

Zanthoxylum avicennae extracts inhibit cell proliferation through protein phosphatase 2A activation in HA22T human hepatocellular carcinoma cells in vitro and in vivo

“…The loss of p53 function allows cells with damaged DNA to continue to proliferate and, therefore, it is associated with tumor progression (14). There is increasing evidence supporting p53 as an attractive target in cancer therapy (15). Our results revealed that YBBEs treatment resulted in a dosedependent increase in p53 level.…”

Differential regulation of the p73 cistrome by mammalian target of rapamycin reveals transcriptional programs of mesenchymal differentiation and tumorigenesis

“…Recent studies show that p73 can be engaged to activate p53 apoptotic pathways in tumor cells that have mutated p53 (22). There has been substantial interest both in drugs that target p73 and in potential prognostic markers of p73 activity.…”

Pirh2

“…8 In response to DNA damage, p53 activates numerous downstream transcriptional targets involved in cell cycle arrest and apoptosis, such as p21, Puma, Bax, and Noxa. 9 The levels and activity p53 in the cell are largely regulated through its posttranslational modifications, such as ubiquitylation, phosphorylation, and acetylation. Monoubiquitylation of p53 can result in its export from the nucleus and its mitochondrial translocation, thus preventing it from acting as a transcription factor, while allowing it to induce mitochondrial mediated apoptosis.…”