Metabolic Regulation by p53 Family Members
Authors: Celia R. Berkers, Oliver D.K. Maddocks, Eric C. Cheung, Inbal Mor, Karen H. Vousden
Journal: Cell Metabolism (2013)

The function of p53 is best understood in response to genotoxic stress, but increasing evidence suggests that p53 also plays a key role in the regulation of metabolic homeostasis. p53 and its family members directly influence various metabolic pathways, enabling cells to respond to metabolic stress. These functions are likely to be important for restraining the development of cancer but could also have a profound effect on the development of metabolic diseases, including diabetes. A better understanding of the metabolic functions of p53 family members may aid in the identification of therapeutic targets and reveal novel uses for p53-modulating drugs. The function of p53 is best understood in response to genotoxic stress, but increasing evidence suggests that p53 also plays a key role in the regulation of metabolic homeostasis. p53 and its family members directly influence various metabolic pathways, enabling cells to respond to metabolic stress. These functions are likely to be important for restraining the development of cancer but could also have a profound effect on the development of metabolic diseases, including diabetes. A better understanding of the metabolic functions of p53 family members may aid in the identification of therapeutic targets and reveal novel uses for p53-modulating drugs. The transcription factor p53 is best known for its role as a tumor suppressor, and a wealth of evidence underscores the importance of p53 in inhibiting cancer development (Vousden and Prives, 2009Vousden K.H. Prives C. Blinded by the Light: The Growing Complexity of p53.Cell. 2009; 137: 413-431Abstract Full Text Full Text PDF PubMed Scopus (936) Google Scholar). Mice lacking p53 are prone to the development of early-onset spontaneous tumors (Donehower et al., 1992Donehower L.A. Harvey M. Slagle B.L. McArthur M.J. Montgomery Jr., C.A. Butel J.S. Bradley A. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours.Nature. 1992; 356: 215-221Crossref PubMed Scopus (2761) Google Scholar). In most human cancers, p53 function is lost (Hollstein et al., 1991Hollstein M. Sidransky D. Vogelstein B. Harris C.C. p53 mutations in human cancers.Science. 1991; 253: 49-53Crossref PubMed Google Scholar), whereas patients that inherit one mutant TP53 allele display an enormously increased cancer risk, a condition known as Li-Fraumeni syndrome (Varley, 2003Varley J.M. Germline TP53 mutations and Li-Fraumeni syndrome.Hum. Mutat. 2003; 21: 313-320Crossref PubMed Scopus (210) Google Scholar). As a key component in the cellular response to stress, p53 is activated by numerous intrinsic and extrinsic stress signals, including genotoxic damage, oncogene activation, loss of normal cell contacts, and nutrient or oxygen deprivation—many of which may be encountered during malignant transformation (Horn and Vousden, 2007Horn H.F. Vousden K.H. Coping with stress: multiple ways to activate p53.Oncogene. 2007; 26: 1306-1316Crossref PubMed Scopus (189) Google Scholar). The outcome of the p53-mediated stress response depends on cell type and context as well as the extent, duration, and origin of the stress. Severe or sustained stress accompanied by irreversible damage, such as extreme genotoxic damage or the activation of oncogenes, results in the induction of cell death or senescence. Such responses effectively eliminate the affected cells, thus limiting the inappropriate accumulation of cells with heritable genomic damage and inhibiting malignant development. On the other hand, mild stress results in a subtler p53 response consistent with repairing or preventing damage. In such cases, p53 may engage antioxidant responses in order to decrease ROS levels or participate in DNA damage repair processes while inducing a transient cell-cycle arrest, thereby allowing cells to survive safely until the damage has been resolved. Transient metabolic stresses—such as fluctuations in oxygen or nutrient availability—also trigger a more adaptive response, in which p53 induces metabolic remodelling and promotes catabolism, while coordinating a decrease in proliferation and cell growth (Figure 1) (Jones et al., 2005Jones R.G. Plas D.R. Kubek S. Buzzai M. Mu J. Xu Y. Birnbaum M.J. Thompson C.B. AMP-activated protein kinase induces a p53-dependent metabolic checkpoint.Mol. Cell. 2005; 18: 283-293Abstract Full Text Full Text PDF PubMed Scopus (674) Google Scholar, Scherz-Shouval et al., 2010Scherz-Shouval R. Weidberg H. Gonen C. Wilder S. Elazar Z. Oren M. p53-dependent regulation of autophagy protein LC3 supports cancer cell survival under prolonged starvation.Proc. Natl. Acad. Sci. USA. 2010; 107: 18511-18516Crossref PubMed Scopus (61) Google Scholar, Maddocks et al., 2013Maddocks O.D.K. Berkers C.R. Mason S.M. Zheng L. Blyth K. Gottlieb E. Vousden K.H. Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells.Nature. 2013; 493: 542-546Crossref PubMed Scopus (74) Google Scholar). These metabolic functions of p53 are emerging as important components of the p53 response that not only aid in maintaining normal cellular homeostasis but also contribute to the control of tumor development. The mechanisms through which p53 is activated by metabolic and other stress signals are complex and have been reviewed elsewhere (Kruse and Gu, 2009Kruse J.P. Gu W. Modes of p53 regulation.Cell. 2009; 137: 609-622Abstract Full Text Full Text PDF PubMed Scopus (576) Google Scholar). Once activated, p53 primarily exerts its functions by acting as a transcription factor, regulating the expression of both genes and microRNAs (miRNAs). p53 has also been reported to possess cytosolic functions. For example, cytoplasmic p53 has been reported to inhibit autophagy (Tasdemir et al., 2008Tasdemir E. Maiuri M.C. Galluzzi L. Vitale I. Djavaheri-Mergny M. D'Amelio M. Criollo A. Morselli E. Zhu C. Harper F. et al.Regulation of autophagy by cytoplasmic p53.Nat. Cell Biol. 2008; 10: 676-687Crossref PubMed Scopus (440) Google Scholar, Morselli et al., 2009Morselli E. Galluzzi L. Kepp O. Vicencio J.-M. Criollo A. Maiuri M.C. Kroemer G. Anti- and pro-tumor functions of autophagy.Biochim. Biophys. Acta. 2009; 1793: 1524-1532Crossref PubMed Scopus (142) Google Scholar, Maiuri et al., 2010Maiuri M.C. Galluzzi L. Morselli E. Kepp O. Malik S.A. Kroemer G. Autophagy regulation by p53.Curr. Opin. Cell Biol. 2010; 22: 181-185Crossref PubMed Scopus (164) Google Scholar), interact with Bcl2 family members to promote apoptosis (reviewed in Green and Kroemer, 2009Green D.R. Kroemer G. Cytoplasmic functions of the tumour suppressor p53.Nature. 2009; 458: 1127-1130Crossref PubMed Scopus (374) Google Scholar), promote necrosis by opening the mitochondrial permeability transition pore (Vaseva et al., 2012Vaseva A.V. Marchenko N.D. Ji K. Tsirka S.E. Holzmann S. Moll U.M. p53 opens the mitochondrial permeability transition pore to trigger necrosis.Cell. 2012; 149: 1536-1548Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar), and regulate glucose metabolism by binding to glucose-6-phosphate dehydrogenase (G6PDH) (Jiang et al., 2011Jiang P. Du W. Wang X. Mancuso A. Gao X. Wu M. Yang X. p53 regulates biosynthesis through direct inactivation of glucose-6-phosphate dehydrogenase.Nat. Cell Biol. 2011; 13: 310-316Crossref PubMed Scopus (127) Google Scholar). Hence, the outcome of p53 activation is complicated, and cell-fate decisions are mediated by transcription-dependent and -independent responses that can vary according to the level and posttranslational modifications of p53 and its interaction with other proteins, including other transcription factors (we will return to this theme later). Alterations in metabolism are increasingly regarded as essential for tumor progression, and many reports suggest that tumor cells become dependent on this metabolic remodelling for their growth and survival (Vander Heiden et al., 2009Vander Heiden M.G. Cantley L.C. Thompson C.B. Understanding the Warburg effect: the metabolic requirements of cell proliferation.Science. 2009; 324: 1029-1033Crossref PubMed Scopus (2149) Google Scholar, Ward and Thompson, 2012Ward P.S. Thompson C.B. Metabolic reprogramming: a cancer hallmark even warburg did not anticipate.Cancer Cell. 2012; 21: 297-308Abstract Full Text Full Text PDF PubMed Scopus (347) Google Scholar). Given its central role as a tumor suppressor, it is not surprising that p53 can regulate several aspects of cellular metabolism and thereby counteract many of the metabolic alterations associated with cancer development (Figure 1). p53 interacts with mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK), two master regulators of cellular metabolism, directly influences many key pathways involved in carbohydrate and lipid metabolism, and regulates autophagy and the oxidative stress response. Recently, metabolic roles have also been ascribed to the p53 family members p63 and p73, further broadening the impact of the p53 family on cell metabolism. In this review, we discuss how p53 and its family members regulate cellular metabolism through mechanisms that are not only crucial for restraining the development of cancer but could also profoundly influence other aspects of health and disease, including aging and the development of metabolic disease. The mTOR protein is an important positive regulator of cell growth and proliferation that can influence the development of diabetes, aging, and cancer (Zoncu et al., 2011Zoncu R. Efeyan A. Sabatini D.M. mTOR: from growth signal integration to cancer, diabetes and ageing.Nat. Rev. Mol. Cell Biol. 2011; 12: 21-35Crossref PubMed Scopus (1091) Google Scholar). mTOR forms two multimeric protein complexes, each with distinct functions (Laplante and Sabatini, 2009Laplante M. Sabatini D.M. mTOR signaling at a glance.J. Cell Sci. 2009; 122: 3589-3594Crossref PubMed Scopus (424) Google Scholar). The mTORC1 complex (consisting of mTOR, Deptor, mLST8 [GβL], PRAS40, and Raptor) has been studied extensively. Its downstream effectors control cell growth and energy metabolism by regulating protein translation and synthesis, mitochondrial biogenesis, lipid synthesis, and autophagy (Howell and Manning, 2011Howell J.J. Manning B.D. mTOR couples cellular nutrient sensing to organismal metabolic homeostasis.Trends Endocrinol. Metab. 2011; 22: 94-102Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar). The functions of mTORC2 (consisting of mTOR, Deptor, mLST8 [GβL], Rictor, Sin1, and Protor-1) are less well defined but include the regulation of the cytoskeleton (Jacinto et al., 2004Jacinto E. Loewith R. Schmidt A. Lin S. Rüegg M.A. Hall A. Hall M.N. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive.Nat. Cell Biol. 2004; 6: 1122-1128Crossref PubMed Scopus (851) Google Scholar) and cell survival (Berchtold and Walther, 2009Berchtold D. Walther T.C. TORC2 plasma membrane localization is essential for cell viability and restricted to a distinct domain.Mol. Biol. Cell. 2009; 20: 1565-1575Crossref PubMed Scopus (79) Google Scholar). mTORC1 is active in the presence of both adequate growth conditions (the availability of nutrients, oxygen, and energy) and mitogens that positively signal for cell division. Conversely, mTORC1 is inhibited by the absence of nutrients or adequate growth conditions and by cellular stresses, which can introduce genomic damage during the process of cell division (Sengupta et al., 2010Sengupta S. Peterson T.R. Sabatini D.M. Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress.Mol. Cell. 2010; 40: 310-322Abstract Full Text Full Text PDF PubMed Scopus (404) Google Scholar). Consequently, a number of important signaling pathways converge on and coregulate mTORC1 activity (Figure 2), including the IGF/AKT/PI3K growth-factor-signaling pathway and the p53 stress-signaling pathway. The presence of nutrients and energy can be sensed by mTORC1 via various mechanisms. For example, energetic stress signals to mTORC1 via the cellular fuel sensor AMPK. The activation of AMPK (in response to an increase in the AMP to ATP ratio) exerts an inhibitory effect on mTORC1 (Hardie et al., 2012Hardie D.G. Ross F.A. Hawley S.A. AMPK: a nutrient and energy sensor that maintains energy homeostasis.Nat. Rev. Mol. Cell Biol. 2012; 13: 251-262Crossref PubMed Scopus (401) Google Scholar) and coordinates activities that allow cells to adapt to metabolic stress. mTORC1 can also be activated in an amino-acid-dependent manner. The presence of amino acids stimulates the recruitment of mTORC1 to the late endosomal and lysosomal compartments, which enables mTORC1 to interact with sensors of growth factor signaling (Zoncu et al., 2011Zoncu R. Efeyan A. Sabatini D.M. mTOR: from growth signal integration to cancer, diabetes and ageing.Nat. Rev. Mol. Cell Biol. 2011; 12: 21-35Crossref PubMed Scopus (1091) Google Scholar). By integrating amino acid sensing with growth factor signaling, this mechanism ensures that mTORC1 is only activated in the presence of both. Given the influence of mTORC1 signaling, it is unsurprising that there are multiple points of crosstalk with the p53 pathway, providing a reciprocal network that is integral to cellular homeostasis (Figure 2). p53 is activated in response to stress, so it generally exerts an inhibitory effect upstream on mTORC1 in order to shut down cell growth, cell division, and energy consumption under adverse conditions. p53 promotes the expression of sestrins, which can activate AMPK (Budanov and Karin, 2008Budanov A.V. Karin M. p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling.Cell. 2008; 134: 451-460Abstract Full Text Full Text PDF PubMed Scopus (346) Google Scholar), and thereby inhibit mTORC1 (Feng et al., 2005Feng Z. Zhang H. Levine A.J. Jin S. The coordinate regulation of the p53 and mTOR pathways in cells.Proc. Natl. Acad. Sci. USA. 2005; 102: 8204-8209Crossref PubMed Scopus (531) Google Scholar). Other transcriptional targets of p53 that can negatively regulate mTORC1 include AMPKβ, TSC2, IGF-BP3, PTEN, and Plk2, all of which are induced by genotoxic stress (Feng et al., 2007Feng Z. Hu W. de Stanchina E. Teresky A.K. Jin S. Lowe S. Levine A.J. The regulation of AMPK beta1, TSC2, and PTEN expression by p53: stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1-AKT-mTOR pathways.Cancer Res. 2007; 67: 3043-3053Crossref PubMed Scopus (214) Google Scholar, Matthew et al., 2009Matthew E.M. Hart L.S. Astrinidis A. Navaraj A. Dolloff N.G. Dicker D.T. Henske E.P. El-Deiry W.S. The p53 target Plk2 interacts with TSC proteins impacting mTOR signaling, tumor growth and chemosensitivity under hypoxic conditions.Cell Cycle. 2009; 8: 4168-4175Crossref PubMed Google Scholar). Nongenotoxic p53 activation by nutlin-3a has also been shown to lead to mTOR inhibition via AMPK activation (Drakos et al., 2009Drakos E. Atsaves V. Li J. Leventaki V. Andreeff M. Medeiros L.J. Rassidakis G.Z. Stabilization and activation of p53 downregulates mTOR signaling through AMPK in mantle cell lymphoma.Leukemia. 2009; 23: 784-790Crossref PubMed Scopus (29) Google Scholar). Although nongenotoxic activation of p53 initially induces a cell-cycle arrest, the ability of p53 to inhibit mTOR in parallel is important in determining the eventual outcome of the p53 response. Cells that sustain mTOR activity (such as through the deletion of TSC2) progress to irreversible senescence, a process named geroconversion, whereas cells in which mTOR is inhibited (for example, through p53 activation or under hypoxia) ultimately achieve a reversible quiescent state (Korotchkina et al., 2010Korotchkina L.G. Leontieva O.V. Bukreeva E.I. Demidenko Z.N. Gudkov A.V. Blagosklonny M.V. The choice between p53-induced senescence and quiescence is determined in part by the mTOR pathway.Aging (Albany NY). 2010; 2: 344-352PubMed Google Scholar, Leontieva et al., 2012Leontieva O.V. Natarajan V. Demidenko Z.N. Burdelya L.G. Gudkov A.V. Blagosklonny M.V. Hypoxia suppresses conversion from proliferative arrest to cellular senescence.Proc. Natl. Acad. Sci. USA. 2012; 109: 13314-13318Crossref PubMed Scopus (57) Google Scholar). The intriguing suggestion here is that, whereas p53 promotes quiescence, it suppresses geroconversion and senescence (by inhibiting mTOR), which may contribute to tumor suppression by preventing the induction of senescence-associated cancer-promoting responses (Blagosklonny, 2012Blagosklonny M.V. Tumor suppression by p53 without apoptosis and senescence: conundrum or rapalog-like gerosuppression?.Aging (Albany NY). 2012; 4: 450-455PubMed Google Scholar). The fact that AMPK can act both upstream and downstream of p53 adds another level of complexity to the p53-mTORC1-AMPK signaling pathways. As described above, during genotoxic stress and nongenotoxic activation of p53, AMPK can be activated downstream of p53 to inhibit mTORC1. However, during energetic stress, AMPK acts upstream of p53, and the inhibition of mTORC1 (by AMPK) occurs in concert with the AMPK-dependent activation of p53 via serine-15 phosphorylation (Imamura et al., 2001Imamura K. Ogura T. Kishimoto A. Kaminishi M. Esumi H. Cell cycle regulation via p53 phosphorylation by a 5′-AMP activated protein kinase activator, 5-aminoimidazole- 4-carboxamide-1-beta-D-ribofuranoside, in a human hepatocellular carcinoma cell line.Biochem. Biophys. Res. Commun. 2001; 287: 562-567Crossref PubMed Scopus (198) Google Scholar, Jones et al., 2005Jones R.G. Plas D.R. Kubek S. Buzzai M. Mu J. Xu Y. Birnbaum M.J. Thompson C.B. AMP-activated protein kinase induces a p53-dependent metabolic checkpoint.Mol. Cell. 2005; 18: 283-293Abstract Full Text Full Text PDF PubMed Scopus (674) Google Scholar). This signal establishes a p53-dependent G1-S checkpoint that prevents S phase entry when cellular energy supplies are inadequate to support the considerable demands of cell division, resulting in a transient cell-cycle arrest. Furthermore, in hepatocellular carcinoma cells, AMPK has been shown to exert an inhibitory effect on the p53 deacetylase Sirt1, thereby enhancing p53 acetylation and activation (Lee et al., 2012aLee C.-W. Wong L.L.-Y. Tse E.Y.-T. Liu H.-F. Leong V.Y.-L. Lee J.M.-F. Hardie D.G. Ng I.O.-L. Ching Y.P. AMPK promotes p53 acetylation via phosphorylation and inactivation of SIRT1 in liver cancer cells.Cancer Res. 2012; 72: 4394-4404Crossref PubMed Scopus (37) Google Scholar). These studies suggest that AMPK can activate p53 via various mechanisms. However, AMPK has also been shown to activate Sirt1 and enhance the deacetylation of Sirt1 targets in skeletal muscle cells (Cantó et al., 2009Cantó C. Gerhart-Hines Z. Feige J.N. Lagouge M. Noriega L. Milne J.C. Elliott P.J. Puigserver P. Auwerx J. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity.Nature. 2009; 458: 1056-1060Crossref PubMed Scopus (769) Google Scholar), indicating that the ability of AMPK to activate p53 via this route may be tissue- and context-dependent. Cellular homeostasis necessitates reciprocal and flexible signaling between the mTOR and p53 pathways in order to balance adequate stress response with the requirement for growth and proliferation (Feng and Levine, 2010Feng Z. Levine A.J. The regulation of energy metabolism and the IGF-1/mTOR pathways by the p53 protein.Trends Cell Biol. 2010; 20: 427-434Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar). Indeed, like AMPK, mTORC1 not only acts downstream of p53 but can also influence p53 activity. For example, survival signaling through the Notch1 receptor, constitutive active forms of which have oncogenic activity, activates mTORC1 via PI3K and AKT, resulting in the inhibition of p53 activity by eIF4E, a translation initiation factor downstream of mTORC1 (Mungamuri et al., 2006Mungamuri S.K. Yang X. Thor A.D. Somasundaram K. Survival signaling by Notch1: mammalian target of rapamycin (mTOR)-dependent inhibition of p53.Cancer Res. 2006; 66: 4715-4724Crossref PubMed Scopus (148) Google Scholar). Conversely, constitutive mTORC1 activation has been shown to activate p53 by enhancing p53 translation (Lee et al., 2007Lee C.-H. Inoki K. Karbowniczek M. Petroulakis E. Sonenberg N. Henske E.P. Guan K.L. Constitutive mTOR activation in TSC mutants sensitizes cells to energy starvation and genomic damage via p53.EMBO J. 2007; 26: 4812-4823Crossref PubMed Scopus (81) Google Scholar) and inducing the expression of alternative reading frame (ARF), a small protein that inhibits MDM2, thus stabilizing p53 in response to oncogene activation (Miceli et al., 2012Miceli A.P. Saporita A.J. Weber J.D. Hypergrowth mTORC1 signals translationally activate the ARF tumor suppressor checkpoint.Mol. Cell. Biol. 2012; 32: 348-364Crossref PubMed Scopus (11) Google Scholar). This suggests that abnormal signaling through mTOR (a sign of malignant transformation) activates p53 (Feng and Levine, 2010Feng Z. Levine A.J. The regulation of energy metabolism and the IGF-1/mTOR pathways by the p53 protein.Trends Cell Biol. 2010; 20: 427-434Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar). Interestingly, AKT-induced senescence occurs via mTORC1-dependent regulation of p53 translation and stabilization of p53 protein (Astle et al., 2012Astle M.V. Hannan K.M. Ng P.Y. Lee R.S. George A.J. Hsu A.K. Haupt Y. Hannan R.D. Pearson R.B. AKT induces senescence in human cells via mTORC1 and p53 in the absence of DNA damage: implications for targeting mTOR during malignancy.Oncogene. 2012; 31: 1949-1962Crossref PubMed Scopus (27) Google Scholar), further supporting the notion that oncogenic signaling can activate p53 via mTOR. When a more restrained p53 response is required (for example, in response to energetic stress), a feedback mechanism involving both AMPK and mTOR may aid in mounting a transient and self-limiting p53 response. p53 activation by 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR), an activator of AMPK, has been shown to be attenuated by the inhibition of mTORC1, suggesting that a self-limiting feedback loop exists whereby AMPK activation simultaneously triggers rapid p53 activation (via serine-15 phosphorylation) and inhibition of mTOR, which eventually shuts down p53 translation (Lee et al., 2007Lee C.-H. Inoki K. Karbowniczek M. Petroulakis E. Sonenberg N. Henske E.P. Guan K.L. Constitutive mTOR activation in TSC mutants sensitizes cells to energy starvation and genomic damage via p53.EMBO J. 2007; 26: 4812-4823Crossref PubMed Scopus (81) Google Scholar). However, such experiments should be interpreted with caution, given that AICAR is an intermediate in nucleotide synthesis, the imbalance of which has been shown to activate p53 (Linke et al., 1996Linke S.P. Clarkin K.C. Di Leonardo A. Tsou A. Wahl G.M. A reversible, p53-dependent G0/G1 cell cycle arrest induced by ribonucleotide depletion in the absence of detectable DNA damage.Genes Dev. 1996; 10: 934-947Crossref PubMed Google Scholar). During some forms of metabolic stress, the mTOR and p53 pathways may also operate independently (Maddocks et al., 2013Maddocks O.D.K. Berkers C.R. Mason S.M. Zheng L. Blyth K. Gottlieb E. Vousden K.H. Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells.Nature. 2013; 493: 542-546Crossref PubMed Scopus (74) Google Scholar). Therefore, it is vital to view and interpret the interplay between p53 and mTOR with careful consideration for the specific context and tissue type. Glucose is a major carbon source for mammalian cells. Once it is taken up by the cell, glucose is broken down to pyruvate in the cytosol, a process known as glycolysis, which yields a limited amount of ATP. In most normal (quiescent) cells, pyruvate is subsequently fed into the mitochondrial tricarboxylic acid (TCA) cycle in order to generate NADH and FADH2, which, in turn, can be used for further ATP production via the highly efficient process of oxidative phosphorylation (OXPHOS). However, the majority of cancer cells display alterations in glucose metabolism (Ward and Thompson, 2012Ward P.S. Thompson C.B. Metabolic reprogramming: a cancer hallmark even warburg did not anticipate.Cancer Cell. 2012; 21: 297-308Abstract Full Text Full Text PDF PubMed Scopus (347) Google Scholar). Often, glycolysis is the preferred pathway for producing energy, even under normal aerobic conditions, and pyruvate is converted primarily to lactate. This shift from mitochondrial respiration to aerobic glycolysis is known as the Warburg effect, and this effect is thought to help satisfy the altered metabolic needs of tumor cells. Their high rate of proliferation requires not only increased amounts of energy but also the rapid production of building blocks necessary for growth and the control of oxidative stress for maximal survival during growth (Beaconsfield and Reading, 1964Beaconsfield P. Reading H.W. Pathways Of Glucose Metabolism And Nucleic Acid Synthesis.Nature. 1964; 202: 464-466Crossref PubMed Scopus (8) Google Scholar, Boros et al., 1998Boros L.G. Lee P.W. Brandes J.L. Cascante M. Muscarella P. Schirmer W.J. Melvin W.S. Ellison E.C. Nonoxidative pentose phosphate pathways and their direct role in ribose synthesis in tumors: is cancer a disease of cellular glucose metabolism?.Med. Hypotheses. 1998; 50: 55-59Abstract Full Text PDF PubMed Scopus (52) Google Scholar). Intermediates from glycolysis can serve as precursors for de novo amino acid, lipid, and nucleotide synthesis and to generate reducing agents that are crucial for maintaining the cellular redox state. For example, an important secondary pathway that branches from glycolysis is the pentose phosphate pathway (PPP), which uses glucose-6-phosphate in reactions that ultimately produce both NADPH and ribose-5-phosphate (R5P). NADPH is an essential reducing agent in many biosynthetic reactions, including de novo lipid synthesis, and helps to protect against oxidative stress by regenerating reduced glutathione (GSH). R5P is a critical component in the de novo synthesis of nucleotides and nucleic acids. The role of the PPP is particularly evident in cells or tissues that undergo proliferation, such as cancer tissues (Beaconsfield et al., 1965Beaconsfield P. Ginsburg J. Kosinski Z. Glucose Metabolism Via The Pentose Phosphate Pathway Relative To Cell Replication And Immunological Response.Nature. 1965; 205: 50-51Crossref PubMed Scopus (3) Google Scholar, Wamelink et al., 2008Wamelink M.M. Struys E.A. Jakobs C. The biochemistry, metabolism and inherited defects of the pentose phosphate pathway: a review.J. Inherit. Metab. Dis. 2008; 31: 703-717Crossref PubMed Scopus (75) Google Scholar; for review see Tong et al., 2009Tong X. Zhao F. Thompson C.B. The molecular determinants of de novo nucleotide biosynthesis in cancer cells.Curr. Opin. Genet. Dev. 2009; 19: 32-37Crossref PubMed Scopus (81) Google Scholar) but also, for example, in regenerating liver tissues (Beaconsfield et al., 1965Beaconsfield P. Ginsburg J. Kosinski Z. Glucose Metabolism Via The Pentose Phosphate Pathway Relative To Cell Replication And Immunological Response.Nature. 1965; 205: 50-51Crossref PubMed Scopus (3) Google Scholar, Ledda-Columbano et al., 1985Ledda-Columbano G.M. Columbano A. Dessì S. Coni P. Chiodino C. Pani P. Enhancement of cholesterol synthesis and pentose phosphate pathway activity in proliferating hepatocyte nodules.Carcinogenesis. 1985; 6: 1371-1373Crossref PubMed Google Scholar). Furthermore, the importance of the PPP in cancer is highlighted in various drug resistance studies that showed that drug-resistant cancer cells often have an elevated PPP activity in comparison to drug-sensitive cells (Gessner et al., 1990Gessner T. Vaughan L.A. Beehler B.C. Bartels C.J. Baker R.M. Elevated pentose cycle and glucuronyltransferase in daunorubicin-resistant P388 cells.Cancer Res. 1990; 50: 3921-3927PubMed Google Scholar, Fanciulli et al., 1993Fanciulli M. Bruno T. Castiglione S. Del Carlo C. Paggi M.G. Floridi A. Glucose metabolism in adriamycin-sensitive and -resistant LoVo human colon carcinoma cells.Oncol. Res. 1993; 5: 357-362PubMed Google Scholar, Ferretti et al., 1993Ferretti A. Chen L.L. Di Vito M. Barca S. Tombesi M. Cianfriglia M. Bozzi A. Strom R. Podo F. Pentose phosphate pathway alterations in multi-drug resistant leukemic T-cells: 31P NMR and enzymatic studies.Anticancer Res. 1993; 13: 867-872PubMed Google Scholar, McBrayer et al., 2012McBrayer S.K. Yarrington M. Qian J. Feng G. Shanmugam M. Gandhi V. Krett N.L. Rosen S.T. Integrative gene expression profiling reveals G6PD-mediated resistance to RNA-directed nucleoside analogues in B-cell neoplasms.PLoS ONE. 2012; 7: e41455Crossref PubMed Scopus (2) Google Scholar); therefore, the inhibition of the PPP can often inhibit tumor growth (Boros et al., 1997Boros L.G. Puigjaner J. Cascante M. Lee W.N. Brandes J.L. Bassilian S. Yusuf F.I. Williams R.D. Muscarella P. Melvin W.S. Schirmer W.J. Oxythiamine and dehydroepiandrosterone inhibit the nonoxidative synthesis of ribose and tumor cell proliferation.Cancer Res. 1997; 57: 4242-4248PubMed Google Scholar, Ramos-Montoya et al., 2006Ramos-Montoya A. Lee W.N. Bassilian S. Lim S. Trebukhina R.V. Kazhyna M.V. Ciudad C.J. Noé V. Centelles J.J. Cascante M. Pentose phosphate cycle oxidative and nonoxidative balance: A new vulnerable target for overcoming drug resistance in cancer.Int. J. Cancer. 2006; 119: 2733-2741Crossref PubMed Scopus (59) Google Scholar, McBrayer et al., 2012McBrayer S.K. Yarrington M. Qian J. Feng G. Shanmugam M. Gandhi V. Krett N.L. Rosen S.T. Integrative gene expression profiling reveals G6PD-mediated resistance to RNA-directed nucleoside analogues in B-cell neoplasms.PLoS ONE. 2012; 7: e41455Crossref PubMed Scopus (2) Google Scholar). Increased expression of some PPP enzymes, such as transketolase, has been suggested to be a