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p53 aerobics: The major tumor suppressor fuels your workout

2006; Cell Press; Volume: 4; Issue: 1 Linguagem: Inglês

10.1016/j.cmet.2006.06.004

1932-7420

Jan-Philipp Kruse, Wei Gu,

Adipose Tissue and Metabolism

In addition to its role as the central regulator of the cellular stress response, p53 can regulate aerobic respiration via the novel transcriptional target SCO2, a critical regulator of the cytochrome c oxidase complex (Matoba et al., 2006Matoba S. Kang J.G. Patino W.D. Wragg A. Boehm M. Gavrilova O. Hurley P.J. Bunz F. Hwang P.M. Science. 2006; 312 (Published online May 25, 2006): 1650-1653https://doi.org/10.1126/science.1126863Crossref PubMed Scopus (1235) Google Scholar). Loss of p53 results in decreased oxygen consumption and aerobic respiration and promotes a switch to glycolysis, thereby reducing endurance during physical exercise. In addition to its role as the central regulator of the cellular stress response, p53 can regulate aerobic respiration via the novel transcriptional target SCO2, a critical regulator of the cytochrome c oxidase complex (Matoba et al., 2006Matoba S. Kang J.G. Patino W.D. Wragg A. Boehm M. Gavrilova O. Hurley P.J. Bunz F. Hwang P.M. Science. 2006; 312 (Published online May 25, 2006): 1650-1653https://doi.org/10.1126/science.1126863Crossref PubMed Scopus (1235) Google Scholar). Loss of p53 results in decreased oxygen consumption and aerobic respiration and promotes a switch to glycolysis, thereby reducing endurance during physical exercise. p53, often referred to as the “guardian of the genome,” is the most commonly mutated gene in human cancer (Vogelstein et al., 2000Vogelstein B. Lane D. Levine A.J. Nature. 2000; 408: 307-310Crossref PubMed Scopus (5518) Google Scholar). In response to DNA damage or other types of stress, p53 acts as a sequence-specific transcription factor and orchestrates the appropriate cellular response by inducing cell cycle arrest, apoptosis, senescence, or differentiation. While most p53 studies have focused on its role as a tumor suppressor, recent work suggests that p53 might play a role in other aspects of mammalian life, including metabolism as reported by Matoba et al., 2006Matoba S. Kang J.G. Patino W.D. Wragg A. Boehm M. Gavrilova O. Hurley P.J. Bunz F. Hwang P.M. Science. 2006; 312 (Published online May 25, 2006): 1650-1653https://doi.org/10.1126/science.1126863Crossref PubMed Scopus (1235) Google Scholar in Science. Most cancer cells display altered energy metabolism, primarily utilizing glycolysis rather than the more efficient aerobic respiration for their energy needs, a switch known as the Warburg Effect (Warburg, 1930Warburg O. The Metabolism of Tumors. Constable, London1930Google Scholar). Although Warburg's classic hypothesis that cancer results from a change in cellular metabolism has been questionable, his observation of increased glycolysis in cancer is commonly used in clinical practice where positron emission technology (PET) scanning is used to detect tumors through their increased incorporation of the glucose analog 18fluorodeoxyglucose tracer (Gambhir, 2002Gambhir S.S. Nat. Rev. Cancer. 2002; 2: 683-693Crossref PubMed Scopus (1252) Google Scholar). Based on the hypothesis that an alteration in the most commonly disturbed pathway in cancer might cause metabolic changes in cancer cells, Matoba et al., 2006Matoba S. Kang J.G. Patino W.D. Wragg A. Boehm M. Gavrilova O. Hurley P.J. Bunz F. Hwang P.M. Science. 2006; 312 (Published online May 25, 2006): 1650-1653https://doi.org/10.1126/science.1126863Crossref PubMed Scopus (1235) Google Scholar found that p53 plays a direct role in the assembly of the cytochrome c oxidase complex, the major site of oxygen utilization in the eukaryotic cell. To test their hypothesis, the authors initially looked at oxygen-consumption and ATP production in both mice and cell lines with hetero- and homozygous loss of p53 and show that p53 loss results in a dose-dependent defect in oxygen consumption, suggesting decreased mitochondrial respiration. Overall ATP production is not altered and lactic acid levels increase with loss of p53, indicating that glycolysis compensates for the reduction in aerobic energy production. Strikingly, p53−/− mice, while having nearly identical body composition and overall ATP production as wild-type mice, have a marked decrease in exercise stamina as shown by a swim stress test (Matoba et al., 2006Matoba S. Kang J.G. Patino W.D. Wragg A. Boehm M. Gavrilova O. Hurley P.J. Bunz F. Hwang P.M. Science. 2006; 312 (Published online May 25, 2006): 1650-1653https://doi.org/10.1126/science.1126863Crossref PubMed Scopus (1235) Google Scholar). These results suggest that p53 plays a crucial role in ensuring efficient ATP production by aerobic respiration for prolonged exercise (see Figure 1). How does a tumor suppressor involved in cell cycle control and apoptosis regulate energy metabolism? The canonical p53 targets could not explain this glycolytic switch, but careful analysis of p53 expression databases led the authors to identify SCO2 (Synthesis of Cytochrome c Oxidase 2) as a gene upregulated in a p53-dependent manner. SCO2 is required for the assembly of a critical component of the COXII complex, and mutations in the gene result in aerobic respiratory failure. The authors establish SCO2 as a transcriptional target for p53 and demonstrate that p53 loss leads to reduced levels of SCO2 expression in both mice and cell lines. Rescue of endogenous SCO2 levels by expression of exogenous SCO2 in p53-deficient cells restores aerobic respiration, establishing the biological relevance of this regulatory circuit. Hetero- or homozygous deletion of SCO2 phenocopies the impaired respiration in p53 deficient cells, indicating that p53 directly regulates mitochondrial respiration through SCO2. The observation that cells with mutated p53 have impaired respiration could have profound effects on cancer cells, as they require large amounts of energy to allow for continuous uncontrolled proliferation. Loss of p53 and the resulting SCO2-dependent reduction in oxidative respiration might drive cells into glycolysis in order to support increased ATP demand. During tumor growth, cells distal to vasculature have limited oxygen supply, and switching to glycolysis may give these cells a growth advantage, allowing them to continue to proliferate before the onset of angiogenesis. A role in controlling cancer cell metabolism complements recent advances in the p53 field that started to establish the protein as a central control point for stress and nutrient response networks in addition to its role in cell cycle control and apoptosis (reviewed by Levine et al., 2006Levine A. Feng Z. Mak T.W. You H. Jin S. Genes Dev. 2006; 20: 267-275Crossref PubMed Scopus (279) Google Scholar). p53, IGF-1/AKT and TOR are all involved in sensing and integrating nutrient and stress signals and their cross-talk allows an intricate regulation of cell-growth, proliferation and programmed cell death. The study by Matoba et al., 2006Matoba S. Kang J.G. Patino W.D. Wragg A. Boehm M. Gavrilova O. Hurley P.J. Bunz F. Hwang P.M. Science. 2006; 312 (Published online May 25, 2006): 1650-1653https://doi.org/10.1126/science.1126863Crossref PubMed Scopus (1235) Google Scholar identified SCO2 as the first direct transcriptional target of p53 that modulates energy metabolism, adding a layer of complexity by connecting the stress response to energy metabolism. To determine the molecular mechanisms of complicated biological processes such as aging and tumor development, the cross-talk between these pathways will need to be further dissected. The p53-SCO2-respiration axis that connects the tumor suppressor to metabolism is an intriguing addition to the long-established connection between the metabolic state of an organism and cancer development. Calorie restriction (CR) has long been known to negatively regulate both tumor formation, growth, and development (reviewed by Hursting et al., 2003Hursting S.D. Lavigne J.A. Berrigan D. Perkins S.N. Barrett J.C. Annu. Rev. Med. 2003; 54: 131-152Crossref PubMed Scopus (457) Google Scholar). This observation has been of great interest, as CR has also been established as the only exogenous way to extend the lifespan of a number of organisms, including yeast, worms, flies, and rodents (reviewed by Bordon and Guarente, 2005Bordon L. Guarente L. Nat. Rev. Mol. Cell Biol. 2005; 6: 298-305Crossref PubMed Scopus (795) Google Scholar). Members of the SIR2 protein family (Sirtuins), originally identified in yeast, have emerged as key players in regulating longevity, their enzymatic activity being regulated by the NAD/NADH ratio within the cell. Mammalian Sirtuins regulate a number of proteins involved in metabolism and the stress response, including p53 (Luo et al., 2001Luo J. Nikolaev A.Y. Imai S. Chen D. Su F. Shiloh A. Guarente L. Gu W. Cell. 2001; 107: 137-148Abstract Full Text Full Text PDF PubMed Scopus (1786) Google Scholar, Vaziri et al., 2001Vaziri H. Dessain S.K. Ng Eaton E. Imai S.I. Frye R.A. Pandita T.K. Guarente L. Weinberg R.A. Cell. 2001; 107: 149-159Abstract Full Text Full Text PDF PubMed Scopus (2144) Google Scholar) and the Forkhead transcription factors (Brunet et al., 2004Brunet A. Sweeney L.B. Sturgill J.F. Chua K.F. Greer P.L. Lin Y. Tran H. Ross S.E. Mostoslavsky R. Cohen H.Y. et al.Science. 2004; 303: 2011-2015Crossref PubMed Scopus (2424) Google Scholar, Motta et al., 2004Motta M.C. Divecha N. Lemieux M. Kamel C. Chen D. Gu W. Bultsma Y. McBurney M. Guarente L. Cell. 2004; 116: 551-563Abstract Full Text Full Text PDF PubMed Scopus (1127) Google Scholar). It will be interesting to see whether SIRT1, the mammalian SIR2 analog, can modulate the p53-dependent expression of SCO2 and thereby regulate the switch from aerobic respiration to glycolysis. It has been argued that the metabolic switch to glycolysis and an acquired acid resistance of cancer cells could yield a powerful growth advantage, promoting unconstrained proliferation and invasion (Gatenby and Gilles, 2004Gatenby R.A. Gilles R.J. Nature Rev. Cancer. 2004; 4: 891-899Crossref PubMed Scopus (3315) Google Scholar) and the data presented by Matoba et al., 2006Matoba S. Kang J.G. Patino W.D. Wragg A. Boehm M. Gavrilova O. Hurley P.J. Bunz F. Hwang P.M. Science. 2006; 312 (Published online May 25, 2006): 1650-1653https://doi.org/10.1126/science.1126863Crossref PubMed Scopus (1235) Google Scholar suggest that loss of p53 might contribute to this acquired growth advantage. Hanahan and Weinberg have described evading apoptosis, self-sufficiency in growth signals, insensitivity to anti-growth signals, issue invasion/metastasis, limitless replicative potential, and sustained angiogenesis as the six hallmarks of cancer development (Hanahan and Weinberg, 2000Hanahan D. Weinberg R.A. Cell. 2000; 100: 57-70Abstract Full Text Full Text PDF PubMed Scopus (20609) Google Scholar). While a loss of p53 has long-established roles in the evasion of apoptosis and the regulation of replicative potential via cell cycle control, the connection of p53 to the regulation of metabolism constitutes a new aspect of how p53 loss and changes in energy metabolism in general might affect tumor cell growth. This raises the possibility that the energetic switch from aerobic respiration to glycolysis adds an additional hallmark of cancer development or could provide further explanations for existing ones, such as the limitless replicative potential or insensitivity to anti-growth signals. Demonstrating a direct metabolic target for p53 could be of great interest for cancer treatment, as the switch to glycolysis is predominantly observed in cancer cells. Specific activation of p53, for example by drugs like Nutlin-3 (Vassilev et al., 2004Vassilev L.T. Vu B.T. Graves B. Carvajal D. Podlaski F. Filipovic Z. Kong N. Kammlott U. Lukacs C. Klein C. et al.Science. 2004; 303: 844-848Crossref PubMed Scopus (3508) Google Scholar), could result not only in targeting its cell cycle and apoptotic responses, but it could also prevent or inhibit the glycolytic metabolism of cancer. It will be interesting to see whether metabolic changes can be observed in cancer patients with mutations for p53 and whether tumors from these patients have reduced SCO2 and aerobic respiration levels. It would also be intriguing to know whether the loss of functional p53 in humans also reduces their energy and exercise potential as seen in mice. The study by Matoba et al., 2006Matoba S. Kang J.G. Patino W.D. Wragg A. Boehm M. Gavrilova O. Hurley P.J. Bunz F. Hwang P.M. Science. 2006; 312 (Published online May 25, 2006): 1650-1653https://doi.org/10.1126/science.1126863Crossref PubMed Scopus (1235) Google Scholar adds aerobic respiration and endurance control to the already extensive array of p53 functions, establishing that p53 may be more than “the guardian of the genome.”