Restoring expression of wild-type p53 suppresses tumor growth but does not cause tumor regression in mice with a p53 missense mutation

Abstract

The transcription factor p53 is a tumor suppressor. As such, the P53 gene is frequently altered in human cancers. However, over 80% of the P53 mutations found in human cancers are missense mutations that lead to expression of mutant proteins that not only lack p53 transcriptional activity but exhibit new functions as well. Recent studies show that restoration of p53 expression leads to tumor regression in mice carrying p53 deletions. However, the therapeutic efficacy of restoring p53 expression in tumors containing p53 missense mutations has not been evaluated. Here we demonstrate that restoring wild-type p53 expression halted tumor growth in mice inheriting a p53 R172H missense mutation that is equivalent to a P53 missense mutation detected in approximately 6% of human cancers. However, it did not lead to tumor regression, as was observed in mice lacking p53. We further showed that the dominant-negative effect of the mutant p53 encoded by p53 R172H dampened the activity of the restored wild-type p53. We therefore conclude that in a mutant p53 background, p53 restoration has the therapeutic potential to suppress tumor progression. Our findings support using p53 restoration as a strategy to treat human cancers with P53 missense mutations and provide direction for optimizing p53 restoration in cancer therapy. IntroductionThe tumor suppressor p53 is a transcription factor. Upon activation by signals, such as DNA damage, oncogenic stimuli, and hypoxia, wild-type p53 activates the transcription of genes involved in apoptosis, cell cycle arrest, differentiation, and senescence (1, 2). These potent antitumor activities prevent cells with aberrant growth signals from proliferating. Approximately, half of human cancers have P53 gene alterations that result in loss of p53 activity. While a few of these alterations are P53-null mutations, over 80% are P53 missense mutations that lead to expression of mutant p53 proteins (3, 4). Many p53 missense mutants lack p53 transcriptional activity and show gain-of-function activities.In particular, the arginine-to-histidine mutation at codon 175 of the P53 gene (corresponding to p53 R172H in mice) occurs in about 6% of human cancers (5). The p53 R172H mutation has gain-of-function properties, manifested as a tumor metastasis phenotype in p53 R172H heterozygous mice that is lacking in p53 +/-mice (6, 7). Another property of the p53R172H mutant is its dominant-negative effect that silences wild-type p53 under some circumstances (8). Thus, for example, in response to γ-irradiation, mutant p53R172H inactivates wild-type p53 activities (9). Additionally, mutant p53 binds and suppresses the activities of the related proteins, p63 and p73 (7). However, the p53 R172H heterozygous mice that express equal amounts of wild-type and mutant p53 have survival curves identical to those of p53 +/-mice, indicating that

Nanoparticle delivery of anticancer drugs overcomes multidrug resistance in breast cancer

“…Reduced levels of TopoII catalytic activity decreases drug-induced TopoII-mediated cleavage of DNA, which leads to reduction of DNA breaks and lower cytotoxicity in MDR cells (Deffie et al, 1989;Ogiso et al, 2002). Alterations in apoptotic or antiapoptotic pathway such as loss of p53 (a transcription factor) (Oshika et al, 1998;Wang et al, 2011;Saha et al, 2012;Wang et al, 2013), abnormal expression of Bcl-2 family (Youle & Strasser, 2008;Saraswathy & Gong, 2013), increased activity of phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) (PI3k/Akt) (Jin et al, 2003;Zhang & Liu, 2011) and aberrant action of nuclear factor kappa beta (NF-kb) (Bentires-Alj et al, 2003) also play a role in the development of MDR in breast cancer cells.…”

Limiting the power of p53 through the ubiquitin proteasome pathway

“…Reintroduction of functionally active wild-type p53 negatively impacts tumor growth in mice (Martins et al 2006;Xue et al 2007;Wang et al 2011;Li et al 2014). Similarly, p53 gene therapy based on retroviral and adenoviral vectors has been assessed in non-small-cell lung carcinomas (NSCLCs) and Li-Fraumeni syndrome patients and shows some efficacy (Roth et al 1996;Senzer et al 2007;Shi and Zheng 2009).…”

Alive failures behind the windows of cancer therapy

“…The p53 is evident to exert a dominantnegative effect when mutated. It should be noted that, this protein (p53) is not a cell-surface protein or an enzyme, thus the difficulty to target with antibodies or enzyme inhibitors (Kenzelmann Broz and Attardi 2010; Wang et al 2011). The anticancer drug, tenovin-1 and tenovin-6 are evident to affect p53 posttranslational modification by inhibiting the protein deacetylation activities of sirtuins, thereby stabilization of p53 (Lain et al 2008).…”