Wild-type p53 emerges from a latent state and becomes stabilized and activated in response to genotoxic and cellular stress signals, resulting in the transcriptional modulation of multiple genes involved in regulating cell-cycle progression, senescence, and apoptosis. More than 50% of human tumors carry p53 mutations. Most of these are missense mutations that result in loss of tumor-suppressing activities and gain of oncogenic activities, termed ‘gain of function.’ Mutant p53 protein enhances proliferation and survival in cells and tumorigenesis in mice when compared with cells or mice that are p53-deficient.
Suh and colleagues from The University of Texas MD Anderson Cancer Center recently studied the effects of stress signals known to stabilize wild-type p53—oncogene activation, DNA damage, and oxidative stress caused by reactive oxygen species (ROS)—on mutant p53 in mice.1 They found that activation of oncogenes in mice with mutant p53 stabilized the mutant p53.
Stabilization and Survival
This stabilization resulted in more potent tumor phenotypes compared with mice harboring the p53 mutation without oncogene activation, although these phenotypes did not result in reduced survival. However, doxorubicin, a DNA-damaging agent, resulted in stabilization of mutant p53 and decreased survival compared with untreated p53 homozygous mice. Further, γ-irradiation resulted in increased stabilization of mutant p53, multiple tumors, and decreased survival compared with irradiated mice with wild-type p53. The use of an ROS scavenger to reduce ROS levels (which are increased, for example, by radiation therapy) resulted in reduced levels of mutant p53 protein.
These findings are of potentially great importance in terms of selecting treatments for patients with mutant p53. They suggest that outcomes of clinical trials should be analyzed according to p53 status of patients receiving such DNA damaging treatments as doxorubicin and radiation therapy. The results also indicate that the “gain of function” phenotype resulting from stabilized mutant p53 may be overcome by inhibiting ROS-mediated DNA damage and suggest that management of ROS levels may be warranted in patients with mutant p53.
As stated by the authors, “These data suggest that direct knowledge of the p53 status of a patient may be critical in preventing unintended consequences when determining therapeutic strategies. This study also emphasizes the need for individually tailored treatment for cancer patients depending upon their p53 mutation status.” ■
Suh Y-A, et al: Cancer Res 71:7168-7175, 2011.