Drug Resistance Updates 15 (2012) 258–267 Contents lists available at SciVerse ScienceDirect Drug Resistance Updates j o ur nal homep a ge: www.elsevier.com/locate/drup From tumor prevention to therapy: Empowering p53 to fight back Christian Frezza, Carla P. Martins * Medical Research Council Cancer Cell Unit, Hutchison/MRC Research Centre, Hills Road, Cambridge CB2 0XZ, United Kingdom a r t i c l e i n f o Article history: Received 5 September 2012 Received in revised form 6 October 2012 Accepted 6 October 2012 Keywords: p53 Metabolism Tumor suppression Cancer therapy a b s t r a c t 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 rein- statement 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 dis- cuss 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. © 2012 Elsevier Ltd. All rights reserved. 1. p53 and the stressful life of normal cells The realization that p53 acts as a tumor suppressor led to a remarkable surge of interest into the function of this transcription factor, making it one of the most intensively studied proteins to date (Baker et al., 1989; Finlay et al., 1989; Levine and Oren, 2009). The crucial role played by p53 in cellular responses to DNA damage provided the first mechanistic clue into its ability to prevent tumor formation and won it the status of “guardian of the genome” (Lane, 1992). The relevance of p53 as a monitor of genotoxic stress remains undeniable and can be traced back to its evolutionary origins (Lu et al., 2009). But throughout evolution p53 acquired additional functions, some of which are potentially unrelated to genotoxic stress. Indeed, p53 is now perceived as a central regulatory node for a complex network of cellular programs and while all p53 func- tions may contribute to its tumor suppressive activity, their relative contributions may be very distinct. As new roles for p53 are uncov- ered the quest for those relevant for tumor suppression continues and a better understanding of p53 function in normal cells will be essential to achieve this goal. The p53 protein family, which includes p63 (Yang et al., 1998) and p73 (Kaghad et al., 1997), is the descendent of an ancient family of transcription factors that predates the appearance of mul- ticellular organisms (King et al., 2008; Mendoza et al., 2003) and * Corresponding author. Tel.: +44 01223 761230; fax: +44 01223 763241. E-mail address: c.martins@hutchison-mrc.cam.ac.uk (C.P. Martins). thus, their origin is unlikely to be related to tumor suppression. In invertebrates the major role of p53-like genes is to protect genome integrity through the regulation of genotoxic stress responses and meiotic chromosome segregation (Brodsky et al., 2000; Mendoza et al., 2003; Ollmann et al., 2000). In mammals, the expanded fam- ily (p53, p63 and p73) acquired a wider range of responsibilities and while some level of functional redundancy occurs, data from animal models suggest a clear division of tasks. Deficiency for p63 or p73 in mice results in gross developmental defects (Mills et al., 1999; Yang et al., 1999, 2000), highlighting the critical role of these proteins in the regulation of several developmental processes including limb morphogenesis, neurogenesis and epithelial development. In con- trast, and despite a high incidence of neural tube defects in female embryos (Armstrong et al., 1995), the majority of p53-null mice are viable and developmentally normal (Donehower et al., 1992), indicative of a less dominant role for this family member dur- ing development. Other physiological roles for p53 have recently been described and include the regulation of stem cell mainte- nance (Liu et al., 2009; Meletis et al., 2006) and cell differentiation (Lin et al., 2005). Whether these physiologic activities require low, constitutive stress or if they rely on stress-independent mecha- nisms remains unclear. In normal cells wild-type (wt) p53 protein is nearly undetectable in vivo as its levels are tightly controlled through a combination of mechanisms predominantly regulated by MDM2 and MDM4 (Wade et al., 2010). p53 mRNA can never- theless be detected in normal tissues, and in vivo data indicate that such basal levels may be sufficient for the physiologic activity of p53 (Marine et al., 2006). 1368-7646/$ – see front matter © 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.drup.2012.10.001