From tumor prevention to therapy: empowering p53 to fight back

The p53 transcription factor was first described over three decades ago and is one of the most studied proteins, with over 60,000 PubMed listed publications. Despite being first described as an oncogene, p53 has long been recognized as a major tumor suppressor and the most commonly mutated gene in human cancer. The frequent inactivation of p53 in tumors fostered the attractive notion that its functional reinstatement would constitute an effective tumor-specific therapy. Strategies aimed at restoring wild-type p53 function in tumors are being actively pursued and some have reached clinical trials, highlighting the important translational potential of this new field of research. The therapeutic impact of those strategies in human cancer was recently modeled in mice where a clear, even if limited, therapeutic benefit of p53-targeted therapies was established. As unexpected aspects of p53 tumor suppressive function continue to be uncovered, new opportunities arise to further improve p53 therapy outcome. In this review we discuss the in vivo mechanisms underlying p53-mediated tumor prevention, the impact of p53 functional restoration in tumors and how this knowledge may be exploited to improve the efficacy of p53-targeted cancer therapy. A particular emphasis is given to the newly identified metabolic functions of p53.