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• W2052543023 abstract "Cancer metabolism has long been equated with aerobic glycolysis, seen by early biochemists as primitive and inefficient. Despite these early beliefs, the metabolic signatures of cancer cells are not passive responses to damaged mitochondria but result from oncogene-directed metabolic reprogramming required to support anabolic growth. Recent evidence suggests that metabolites themselves can be oncogenic by altering cell signaling and blocking cellular differentiation. No longer can cancer-associated alterations in metabolism be viewed as an indirect response to cell proliferation and survival signals. We contend that altered metabolism has attained the status of a core hallmark of cancer. Cancer metabolism has long been equated with aerobic glycolysis, seen by early biochemists as primitive and inefficient. Despite these early beliefs, the metabolic signatures of cancer cells are not passive responses to damaged mitochondria but result from oncogene-directed metabolic reprogramming required to support anabolic growth. Recent evidence suggests that metabolites themselves can be oncogenic by altering cell signaling and blocking cellular differentiation. No longer can cancer-associated alterations in metabolism be viewed as an indirect response to cell proliferation and survival signals. We contend that altered metabolism has attained the status of a core hallmark of cancer. The propensity for proliferating cells to secrete a significant fraction of glucose carbon through fermentation was first elucidated in yeast. Otto Warburg extended these observations to mammalian cells, finding that proliferating ascites tumor cells converted the majority of their glucose carbon to lactate, even in oxygen-rich conditions. Warburg hypothesized that this altered metabolism was specific to cancer cells, and that it arose from mitochondrial defects that inhibited their ability to effectively oxidize glucose carbon to CO2. An extension of this hypothesis was that dysfunctional mitochondria caused cancer (Koppenol et al., 2011Koppenol W.H. Bounds P.L. Dang C.V. Nat. Rev. Cancer. 2011; 11: 325-337Crossref PubMed Scopus (272) Google Scholar). Warburg's seminal finding has been observed in a wide variety of cancers. These observations have been exploited clinically using 18F-deoxyglucose positron emission tomography (FDG-PET). However, in contrast to Warburg's original hypothesis, damaged mitochondria are not at the root of the aerobic glycolysis exhibited by most tumor cells. Most tumor mitochondria are not defective in their ability to carry out oxidative phosphorylation. Instead, in proliferating cells, mitochondrial metabolism is reprogrammed to meet the challenges of macromolecular synthesis. This possibility was never considered by Warburg and his contemporaries. Advances in cancer metabolism research over the last decade have enhanced our understanding of how aerobic glycolysis and other metabolic alterations observed in cancer cells support the anabolic requirements associated with cell growth and proliferation. It has become clear that anabolic metabolism is under complex regulatory control directed by growth-factor signal transduction in nontransformed cells. Yet despite these advances, the repeated refrain from traditional biochemists is that altered metabolism is merely an indirect phenomenon in cancer, a secondary effect that pales in importance to the activation of primary proliferation and survival signals (Hanahan and Weinberg, 2011Hanahan D. Weinberg R.A. Cell. 2011; 144: 646-674Abstract Full Text Full Text PDF PubMed Scopus (4513) Google Scholar). Most proto-oncogenes and tumor suppressor genes encode components of signal transduction pathways. Their roles in carcinogenesis have traditionally been attributed to their ability to regulate the cell cycle and sustain proliferative signaling while also helping cells evade growth suppression and/or cell death (Hanahan and Weinberg, 2011Hanahan D. Weinberg R.A. Cell. 2011; 144: 646-674Abstract Full Text Full Text PDF PubMed Scopus (4513) Google Scholar). But evidence for an alternative concept, that the primary functions of activated oncogenes and inactivated tumor suppressors are to reprogram cellular metabolism, has continued to build over the past several years. Evidence is also developing for the proposal that proto-oncogenes and tumor suppressors primarily evolved to regulate metabolism. We begin this review by discussing how proliferative cell metabolism differs from quiescent cell metabolism on the basis of active metabolic reprogramming by proto-oncogenes and tumor suppressors. Much of this reprogramming depends on utilizing mitochondria as functional biosynthetic organelles. We then further develop the idea that altered metabolism is a primary feature selected for during tumorigenesis. Recent advances have demonstrated that altered metabolism in cancer extends beyond adaptations to meet the increased anabolic requirements of a growing and dividing cell. Changes in cancer cell metabolism can also influence cellular differentiation status, and in some cases these changes arise from oncogenic alterations in metabolic enzymes themselves. Most nonproliferating, differentiated cells depend on the efficiency of ATP production through oxidative phosphorylation to maintain their integrity. As a result, such cells metabolize glucose to pyruvate through glycolysis, and then completely oxidize most of this pyruvate to CO2 through the tricarboxylic acid (TCA) cycle of the mitochondria, where oxygen is the final acceptor in an electron transport chain that generates an electrochemical gradient facilitating ATP production. The elucidation of the TCA cycle and how cells maximize ATP production to maintain themselves was one of the great discoveries of the last century. In vivo, metazoan cells are surrounded by an abundance of nutrients. However, unlike prokaryotes or single-cell eukaryotes, animal cells are not cell autonomous for nutrient uptake. Instead, just to survive, metazoan cells compete for limiting levels of growth factors that direct nutrient uptake (Rathmell et al., 2000Rathmell J.C. Vander Heiden M.G. Harris M.H. Frauwirth K.A. Thompson C.B. Mol. Cell. 2000; 6: 683-692Abstract Full Text Full Text PDF PubMed Google Scholar). To survive under such conditions, differentiated cells adopt a catabolic metabolism focused on maximizing the efficiency of ATP production from limited nutrients (Deberardinis et al., 2006Deberardinis R.J. Lum J.J. Thompson C.B. J. Biol. Chem. 2006; 281: 37372-37380Crossref PubMed Scopus (78) Google Scholar, Lum et al., 2005Lum J.J. Bauer D.E. Kong M. Harris M.H. Li C. Lindsten T. Thompson C.B. Cell. 2005; 120: 237-248Abstract Full Text Full Text PDF PubMed Scopus (706) Google Scholar, Vander Heiden et al., 2009Vander Heiden M.G. Cantley L.C. Thompson C.B. Science. 2009; 324: 1029-1033Crossref PubMed Scopus (1668) Google Scholar) (Figure 1A ). In contrast, when growth factors are abundant, cells increase their nutrient uptake and adopt an anabolic metabolism (Bauer et al., 2004Bauer D.E. Harris M.H. Plas D.R. Lum J.J. Hammerman P.S. Rathmell J.C. Riley J.L. Thompson C.B. FASEB J. 2004; 18: 1303-1305Crossref PubMed Scopus (0) Google Scholar) (Figure 1B). As a consequence of intracellular abundance of nutrients, growth-factor-stimulated cells adapt to their largesse by initiating cell division in a manner analogous to that of single-cell eukaryotes exposed to nutrient-rich medium (Boer et al., 2010Boer V.M. Crutchfield C.A. Bradley P.H. Botstein D. Rabinowitz J.D. Mol. Biol. Cell. 2010; 21: 198-211Crossref PubMed Scopus (63) Google Scholar, Conlon and Raff, 2003Conlon I. Raff M. J. Biol. 2003; 2: 7Crossref PubMed Google Scholar, Fantes and Nurse, 1977Fantes P. Nurse P. Exp. Cell Res. 1977; 107: 377-386Crossref PubMed Google Scholar). In cancer cells, the instructional signaling pathways downstream of growth factor receptors can be constitutively activated in the absence of extracellular growth factors. The traditional cancer model posits that the altered metabolism associated with cell proliferation occurs as a secondary response to cell cycle and proliferative signaling. In this model, the demand for free energy to sustain transcription and translation drives a decrease in the ATP:ADP ratio, leading to subsequent allosteric effects on rate-limiting metabolic enzymes (Figure 2A ). While traditional allosteric regulation certainly occurs in proliferating cells, strong evidence now exists to support an alternative model. In this supply-based model, changes in metabolic fluxes occur in primary response to growth-factor signaling, independent of changes in ATP and other mechanisms worked out by early biochemists (Figure 2B). The reprogramming of cellular metabolism toward macromolecular synthesis is critical to supplying enough nucleotides, proteins, and lipids for a cell to double its total biomass and then divide to produce two daughter cells. In contrast to the catabolic metabolism of differentiated cells, this anabolic metabolism fundamental to cell growth and proliferation is not focused on maximizing ATP yield. Rather than ATP, proliferating cells are in much greater need of reduced carbon and reduced nitrogen, as well as cytosolic NADPH for reductive biosynthetic reactions. The recognition that proliferating cells do not maximize ATP production through mitochondrial oxidative phosphorylation has contributed to the continuing misconception that proliferating cells, particularly cancer cells, do not utilize mitochondria. In fact, most cancer cells and proliferating normal cells still derive a significant fraction of their ATP through oxidative phosphorylation. However, in proliferating cells, in contrast to quiescent cells, this oxidative phosphorylation-dependent production of ATP appears secondary to the use of mitochondrial enzymes in the synthesis of anabolic precursors. Activation of the PI3K/Akt pathway is perhaps the most common lesion in spontaneous human cancers. Activated PI3K/Akt leads to enhanced glucose uptake and glycolysis (Buzzai et al., 2005Buzzai M. Bauer D.E. Jones R.G. Deberardinis R.J. Hatzivassiliou G. Elstrom R.L. Thompson C.B. Oncogene. 2005; 24: 4165-4173Crossref PubMed Scopus (144) Google Scholar, Elstrom et al., 2004Elstrom R.L. Bauer D.E. Buzzai M. Karnauskas R. Harris M.H. Plas D.R. Zhuang H. Cinalli R.M. Alavi A. Rudin C.M. Thompson C.B. Cancer Res. 2004; 64: 3892-3899Crossref PubMed Scopus (462) Google Scholar). Pivotal to this induction is increased glucose transporter expression on the cell surface, activation of hexokinase to capture glucose intracellularly through phosphorylation, and Akt-induced, phosphofructokinase-2-dependent allosteric activation of phosphofructokinase-1 to commit glucose to glycolytic metabolism (Deprez et al., 1997Deprez J. Vertommen D. Alessi D.R. Hue L. Rider M.H. J. Biol. Chem. 1997; 272: 17269-17275Crossref PubMed Scopus (190) Google Scholar, Gottlob et al., 2001Gottlob K. Majewski N. Kennedy S. Kandel E. Robey R.B. Hay N. Genes Dev. 2001; 15: 1406-1418Crossref PubMed Scopus (451) Google Scholar, Kohn et al., 1996Kohn A.D. Summers S.A. Birnbaum M.J. Roth R.A. J. Biol. Chem. 1996; 271: 31372-31378Crossref PubMed Scopus (794) Google Scholar, Rathmell et al., 2003Rathmell J.C. Fox C.J. Plas D.R. Hammerman P.S. Cinalli R.M. Thompson C.B. Mol. Cell. Biol. 2003; 23: 7315-7328Crossref PubMed Scopus (258) Google Scholar). However, the PI3K/Akt pathway also promotes glucose carbon flux into biosynthetic pathways that rely upon functional mitochondrial metabolism (Figure 3). For example, fatty acid, cholesterol, and isoprenoid synthesis all require acetyl-CoA (Wakil et al., 1957Wakil S.J. Porter J.W. Gibson D.M. Biochim. Biophys. Acta. 1957; 24: 453-461Crossref PubMed Google Scholar). The pyruvate dehydrogenase (PDH) complex that converts glucose-derived pyruvate into acetyl-CoA is solely mitochondrial (Linn et al., 1969Linn T.C. Pettit F.H. Reed L.J. Proc. Natl. Acad. Sci. USA. 1969; 62: 234-241Crossref PubMed Google Scholar). Mitochondrial acetyl-CoA then cannot be directly exported to the cytoplasm but instead must first condense with oxaloacetate to form citrate through the activity of another exclusively mitochondrial enzyme, citrate synthase (Stern et al., 1952Stern J.R. Ochoa S. Lynen F. J. Biol. Chem. 1952; 198: 313-321Abstract Full Text PDF PubMed Google Scholar). Citrate can then be exported to the cytosol, where it can be converted back to acetyl-CoA by ATP-citrate lyase (ACL) (Srere, 1959Srere P.A. J. Biol. Chem. 1959; 234: 2544-2547Abstract Full Text PDF PubMed Google Scholar). Akt facilitates this diversion of mitochondrial citrate from the TCA cycle to acetyl-CoA production by phosphorylating and activating ACL (Bauer et al., 2005Bauer D.E. Hatzivassiliou G. Zhao F. Andreadis C. Thompson C.B. Oncogene. 2005; 24: 6314-6322Crossref PubMed Scopus (140) Google Scholar, Berwick et al., 2002Berwick D.C. Hers I. Heesom K.J. Moule S.K. Tavare J.M. J. Biol. Chem. 2002; 277: 33895-33900Crossref PubMed Scopus (121) Google Scholar, Hatzivassiliou et al., 2005Hatzivassiliou G. Zhao F. Bauer D.E. Andreadis C. Shaw A.N. Dhanak D. Hingorani S.R. Tuveson D.A. Thompson C.B. Cancer Cell. 2005; 8: 311-321Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar). RNAi knockdown or pharmacologic inhibition of ACL is particularly effective at decreasing the in vitro proliferation of cells with increased glucose uptake. ACL knockdown can also diminish Akt-driven tumorigenesis in vivo (Bauer et al., 2005Bauer D.E. Hatzivassiliou G. Zhao F. Andreadis C. Thompson C.B. Oncogene. 2005; 24: 6314-6322Crossref PubMed Scopus (140) Google Scholar, Hatzivassiliou et al., 2005Hatzivassiliou G. Zhao F. Bauer D.E. Andreadis C. Shaw A.N. Dhanak D. Hingorani S.R. Tuveson D.A. Thompson C.B. Cancer Cell. 2005; 8: 311-321Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar). ACL's breakdown of citrate is also pivotal to preventing a cytosolic accumulation of citrate. Citrate is a major negative allosteric regulator of glycolysis (Stryer, 1995Stryer L. Biochemistry.Fourth Edition. W.H. Feeman and Company, New York1995Google Scholar). Taken together, these findings demonstrate that the reprogramming of mitochondrial citrate metabolism is a central aspect of PI3K/Akt oncogenic activity. Downstream of PI3K/Akt, the well-characterized cell growth regulator mTORC1 also has many effects intertwined with mitochondrial metabolism. mTORC1 is best known for enhancing protein synthesis. Several amino acid precursors are derived from the transamination of mitochondrial intermediates. Oxaloacetate can be transaminated to produce aspartate which can serve as a precursor for asparagine, and α-ketoglutarate can be transaminated to produce glutamate, which in turn can be converted to proline, arginine, and glutamine. Most cancers depend on these syntheses rather than exogenous supplies. This is consistent with how most tumors other than childhood leukemia are resistant to the effects of depleting the blood of asparagine through the intravenous use of L-asparaginase (Clarkson et al., 1970Clarkson B. Krakoff I. Burchenal J. Karnofsky D. Golbey R. Dowling M. Oettgen H. Lipton A. Cancer. 1970; 25: 279-305Crossref PubMed Google Scholar, Tallal et al., 1970Tallal L. Tan C. Oettgen H. Wollner N. McCarthy M. Helson L. Burchenal J. Karnofsky D. Murphy M.L. Cancer. 1970; 25: 306-320Crossref PubMed Google Scholar). mTORC1 has also been shown to have direct effects on promoting mitochondrial biogenesis, in part via a transcriptional complex that promotes the function of PGC-1α (Bentzinger et al., 2008Bentzinger C.F. Romanino K. Cloëtta D. Lin S. Mascarenhas J.B. Oliveri F. Xia J. Casanova E. Costa C.F. Brink M. et al.Cell Metab. 2008; 8: 411-424Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar, Cunningham et al., 2007Cunningham J.T. Rodgers J.T. Arlow D.H. Vazquez F. Mootha V.K. Puigserver P. Nature. 2007; 450: 736-740Crossref PubMed Scopus (326) Google Scholar, Ramanathan and Schreiber, 2009Ramanathan A. Schreiber S.L. Proc. Natl. Acad. Sci. USA. 2009; 106: 22229-22232Crossref PubMed Scopus (60) Google Scholar, Schieke et al., 2006Schieke S.M. Phillips D. McCoy Jr., J.P. Aponte A.M. Shen R.F. Balaban R.S. Finkel T. J. Biol. Chem. 2006; 281: 27643-27652Crossref PubMed Scopus (231) Google Scholar). Finally, a study isolating the cell-intrinsic consequences of mTORC1 activation demonstrated that SREBP-mediated de novo lipogenesis is a critical component of mTORC1-driven proliferation (Düvel et al., 2010Düvel K. Yecies J.L. Menon S. Raman P. Lipovsky A.I. Souza A.L. Triantafellow E. Ma Q. Gorski R. Cleaver S. et al.Mol. Cell. 2010; 39: 171-183Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar). As discussed above, de novo lipogenesis in mammalian cells depends on mitochondrial citrate production. Notably, Düvel et al., 2010Düvel K. Yecies J.L. Menon S. Raman P. Lipovsky A.I. Souza A.L. Triantafellow E. Ma Q. Gorski R. Cleaver S. et al.Mol. Cell. 2010; 39: 171-183Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar found that the other major target of mTORC1 activation, hypoxia-inducible factor 1 (HIF-1), is not critical for mTORC1-driven proliferation. This may seem surprising in light of HIF-1's often-cited ability to promote the enhanced glycolysis characteristic of cancer cells. However, HIF-1 activation has the additional effect of inhibiting mitochondrial metabolism of glucose carbon, in part by promoting the expression of pyruvate dehydrogenase kinase 1 (PDK1) to inhibit PDH activity (Kim et al., 2006Kim J.W. Tchernyshyov I. Semenza G.L. Dang C.V. Cell Metab. 2006; 3: 177-185Abstract Full Text Full Text PDF PubMed Scopus (744) Google Scholar, Papandreou et al., 2006Papandreou I. Cairns R.A. Fontana L. Lim A.L. Denko N.C. Cell Metab. 2006; 3: 187-197Abstract Full Text Full Text PDF PubMed Scopus (561) Google Scholar). By diverting pyruvate into lactate, HIF-1 blocks glucose carbon incorporation into mitochondrial citrate which is critical for lipid synthesis (Lum et al., 2007Lum J.J. Bui T. Gruber M. Gordan J.D. DeBerardinis R.J. Covello K.L. Simon M.C. Thompson C.B. Genes Dev. 2007; 21: 1037-1049Crossref PubMed Scopus (111) Google Scholar). This block correlates with the antiproliferative effect of HIF-1 observed in hematopoietic and renal cells (Lum et al., 2007Lum J.J. Bui T. Gruber M. Gordan J.D. DeBerardinis R.J. Covello K.L. Simon M.C. Thompson C.B. Genes Dev. 2007; 21: 1037-1049Crossref PubMed Scopus (111) Google Scholar) and fits with recent genetic evidence of HIF-1 acting as a tumor suppressor in some cancers (Shen et al., 2011Shen C. Beroukhim R. Schumacher S.E. Zhou J. Chang M. Signoretti S. Kaelin Jr., W.G. Cancer Discov. 2011; 1: 222-235Crossref PubMed Scopus (38) Google Scholar). There are cancers that do exhibit decreased flux of glucose-derived pyruvate into the mitochondria relative to normal tissues. However, as will be discussed later in this review, these cancers still rely on mitochondrial metabolic flux. In place of oxidative metabolism of both glucose and glutamine, these cancers preferentially perform reductive and carboxylating biosynthetic reactions from glutamine carbon (Le et al., 2012Le A. Lane A.N. Hamaker M. Bose S. Gouw A. Barbi J. Tsukamoto T. Rojas C.J. Slusher B.S. Zhang H. et al.Cell Metab. 2012; 15: 110-121Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar, Metallo et al., 2012Metallo C.M. Gameiro P.A. Bell E.L. Mattaini K.R. Yang J. Hiller K. Jewell C.M. Johnson Z.R. Irvine D.J. Guarente L. et al.Nature. 2012; 481: 380-384Crossref Scopus (0) Google Scholar, Mullen et al., 2012Mullen A.R. Wheaton W.W. Jin E.S. Chen P.H. Sullivan L.B. Cheng T. Yang Y. Linehan W.M. Chandel N.S. DeBerardinis R.J. Nature. 2012; 481: 385-388Crossref Scopus (0) Google Scholar, Wise et al., 2011Wise D.R. Ward P.S. Shay J.E. Cross J.R. Gruber J.J. Sachdeva U.M. Platt J.M. DeMatteo R.G. Simon M.C. Thompson C.B. Proc. Natl. Acad. Sci. USA. 2011; 108: 19611-19616Crossref PubMed Scopus (109) Google Scholar). Like PI3K, Akt, and mTORC1, the Myc transcription factor has important metabolic roles beyond enhancing glycolysis. Myc promotes mitochondrial gene expression and mitochondrial biogenesis (Li et al., 2005Li F. Wang Y. Zeller K.I. Potter J.J. Wonsey D.R. O'Donnell K.A. Kim J.W. Yustein J.T. Lee L.A. Dang C.V. Mol. Cell. Biol. 2005; 25: 6225-6234Crossref PubMed Scopus (174) Google Scholar). Oncogenic Myc has also been shown to promote the mitochondrial utilization of glutamine by enhancing the expression of glutaminase (GLS), which deamidates glutamine to glutamate. Cells expressing oncogenic Myc are glutamine-addicted and undergo apoptosis when glutamine is withdrawn from the culture medium. While the role of glutamine as a nitrogen donor is important for the proliferation of these cells, their viability depends on glutamine as a carbon source for mitochondrial metabolism (DeBerardinis et al., 2007DeBerardinis R.J. Mancuso A. Daikhin E. Nissim I. Yudkoff M. Wehrli S. Thompson C.B. Proc. Natl. Acad. Sci. USA. 2007; 104: 19345-19350Crossref PubMed Scopus (451) Google Scholar, Fan et al., 2010Fan Y. Dickman K.G. Zong W.X. J. Biol. Chem. 2010; 285: 7324-7333Crossref PubMed Scopus (35) Google Scholar, Gao et al., 2009Gao P. 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These data provide further evidence that reprogrammed glutamine metabolism is critical to the growth and survival of Myc-driven malignancies. Upstream of Myc, RhoGTPases have also been linked to the activation of GLS and glutamine dependence. Either siRNA knockdown or pharmacological inhibition of GLS can inhibit Rho-GTPase-induced transformation and proliferation (Wang et al., 2010Wang J.B. Erickson J.W. Fuji R. Ramachandran S. Gao P. Dinavahi R. Wilson K.F. Ambrosio A.L. Dias S.M. Dang C.V. Cerione R.A. Cancer Cell. 2010; 18: 207-219Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar). The weight of the evidence to date supports the concept that reprogramming of cellular metabolism is a primary and fundamental aspect of transformation resulting from mutations in proto-oncogenes and tumor suppressors. Proliferative metabolism is heavily dependent on the reprogramming of mitochondria to serve a synthetic rather than a degradative role. Metabolic changes associated with proliferating cells do not simply occur passively in response to damaged mitochondria or changes in ATP levels. A related concept concerns the possibility that proto-oncogenes and tumor suppressors arose in evolution as components of metabolic regulation. Consistent with this hypothesis, activation of the tumor suppressor p53 has been shown to be critical for cell survival following glucose depletion (Jones et al., 2005Jones R.G. Plas D.R. Kubek S. Buzzai M. Mu J. Xu Y. Birnbaum M.J. Thompson C.B. Mol. Cell. 2005; 18: 283-293Abstract Full Text Full Text PDF PubMed Scopus (598) Google Scholar). Subsequent reports have linked this metabolic stress response of p53 to increased fatty acid oxidation (Assaily et al., 2011Assaily W. Rubinger D.A. Wheaton K. Lin Y. Ma W. Xuan W. Brown-Endres L. Tsuchihara K. Mak T.W. Benchimol S. Mol. Cell. 2011; 44: 491-501Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar, Zaugg et al., 2011Zaugg K. Yao Y. 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Treatment with the antidiabetic drug metformin, an inhibitor of complex 1 of the mitochondrial electron transport chain (El-Mir et al., 2000El-Mir M.Y. Nogueira V. Fontaine E. Avéret N. Rigoulet M. Leverve X. J. Biol. Chem. 2000; 275: 223-228Crossref PubMed Scopus (344) Google Scholar, Owen et al., 2000Owen M.R. Doran E. Halestrap A.P. Biochem. J. 2000; 348: 607-614Crossref PubMed Scopus (470) Google Scholar), is especially toxic to p53-deficient tumor cells (Buzzai et al., 2007Buzzai M. Jones R.G. Amaravadi R.K. Lum J.J. DeBerardinis R.J. Zhao F. Viollet B. Thompson C.B. Cancer Res. 2007; 67: 6745-6752Crossref PubMed Scopus (330) Google Scholar). Oncogenic mutations in proto-oncogenes can be selected for in tumor populations subjected to metabolic stress. Yun et al., 2009Yun J. Rago C. Cheong I. Pagliarini R. Angenendt P. Rajagopalan H. Schmidt K. Willson J.K. Markowitz S. 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Joseph J. Lopez M. Kalyanaraman B. Mutlu G.M. Budinger G.R. Chandel N.S. Proc. Natl. Acad. Sci. USA. 2010; 107: 8788-8793Crossref PubMed Scopus (198) Google Scholar). In addition to activating oncogenes like Ras, preferentially expressing specific isoforms of metabolic enzymes can provide cancer cells with a mechanism to select for metabolic alterations during tumorigenesis. For example, proliferating cells almost universally express the M2 isoform of pyruvate kinase M (PKM2). Pyruvate kinase is a glycolytic enzyme that converts phosphoenolpyruvate (PEP) to pyruvate, with concomitant generation of ATP. In contrast to the M1 isoform of pyruvate kinase (PKM1) that is the predominant isoform in most adult differentiated tissues, the PKM2 splice variant is the major isoform in embryonic tissues and in all cancer cells examined to date (Mazurek, 2011Mazurek S. Int. J. Biochem. Cell Biol. 2011; 43: 969-980Crossref PubMed Scopus (118) Google Scholar). Other significant genes for proliferative cell metabolism are also alternatively spliced. The phosphofructokinase/fructose-2,6-bisphosphatase B3 gene (PFKFB3) is highly expressed in human tumors and has six splice variants. Two splice variants predominate in high-grade astrocytoma and colon carcinoma and enhance glycolytic flux, while other splice variants are limited to low-grade tumors and normal tissues (Bando et al., 2005Bando H. Atsumi T. Nishio T. Niwa H. Mishima S. Shimizu C. Yoshioka N. Bucala R. Koike T. Clin. Cancer Res. 2005; 11: 5784-5792Crossref PubMed Scopus (45) Google Scholar, Zscharnack et al., 2009Zscharnack K. Kessler R. Bleichert F. Warnke J.P. Eschrich K. Neuropathol. Appl. Neurobiol. 2009; 35: 566-578Crossref PubMed Scopus (4) Google Scholar). An alternatively spliced isoform of GLS may also be important for the mitochondrial glutamine metabolism of tumor cells (Cassago et al., 2012Cassago A. Ferreira A.P. Ferreira I.M. Fornezari C. Gomes E.R. Greene K.S. Pereira H.M. Garratt R.C. Dias S.M. Ambrosio A.L. Proc. Natl. Acad. Sci. USA. 2012; 109: 1092-1097Crossref PubMed Scopus (13) Google Scholar). The most extensively characterized of these alternatively spliced metabolic enzymes remains pyruvate kinase. The preferential expression of PKM2 in proliferating cells suggested a protumorigenic role for this splice variant, and xenograft models subsequently demonstrated that PKM2-expressing cells have a growth advantage in vivo compared with PKM1-expressing cells (Christofk et al., 2008aChristofk H.R. Vander Heiden M.G. Harris M.H. Ramanathan A. Gerszten R.E. Wei R. Fleming M.D. Schreiber S.L. Cantley L.C. Nature. 2008; 452: 230-233Crossref PubMed Scopus (660) Google Scholar). However, in what might seem paradoxical for an isoform associated with proliferating and highly glycolytic cells, PKM2 has intrinsically lower enzymatic activity than PKM1. PKM2 is a" @default.
• W2052543023 created "2016-06-24" @default.
• W2052543023 creator A5027062879 @default.
• W2052543023 creator A5088551754 @default.
• W2052543023 date "2012-03-01" @default.
• W2052543023 modified "2023-10-18" @default.
• W2052543023 title "Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate" @default.
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