Über den stoffwechsel der carcinomzelle. Biochem. Zeitschr
152, 309–344 (1924).
Koppenol, W. H., Bounds, P. L. & Dang, C. V.
Otto Warburg's contributions to current concepts of cancer metabolism. Nature Rev. Cancer
11, 325–337 (2011).
Ben-Haim, S. & Ell, P.
18F-FDG PET and PET/CT in the evaluation of cancer treatment response. J. Nucl. Med.
50, 88–99 (2009).
Vander Heiden, M. G., Cantley, L. C. & Thompson, C. B.
Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science
324, 1029–1033 (2009).
Schulze, A. & Harris, A. L.
How cancer metabolism is tuned for proliferation and vulnerable to disruption. Nature
491, 364–373 (2012).
Deconvoluting the context-dependent role for autophagy in cancer. Nature Rev. Cancer
12, 401–410 (2012). This review provides an extensive discussion on the context-dependent role of autophagy in oncogenesis, tumour progression and response to therapy.
Hanahan, D. & Weinberg, R. A.
The hallmarks of cancer. Cell
100, 57–70 (2000).
Hanahan, D. & Weinberg, R. A.
Hallmarks of cancer: the next generation. Cell
144, 646–674 (2011).
Vander Heiden, M. G.
Targeting cancer metabolism: a therapeutic window opens. Nature Rev. Drug Discov.
10, 671–684 (2011).
Tennant, D. A., Duran, R. V. & Gottlieb, E.
Targeting metabolic transformation for cancer therapy. Nature Rev. Cancer
10, 267–277 (2010).
Chabner, B. A. & Roberts, T. G. Jr.
Timeline: chemotherapy and the war on cancer. Nature Rev. Cancer
5, 65–72 (2005).
Khandekar, M. J., Cohen, P. & Spiegelman, B. M.
Molecular mechanisms of cancer development in obesity. Nature Rev. Cancer
11, 886–895 (2011).
The insulin and insulin-like growth factor receptor family in neoplasia: an update. Nature Rev. Cancer
12, 159–169 (2012).
Evans, J. M., Donnelly, L. A., Emslie-Smith, A. M., Alessi, D. R. & Morris, A. D.
Metformin and reduced risk of cancer in diabetic patients. BMJ
330, 1304–1305 (2005).
Li, D., Yeung, S. C., Hassan, M. M., Konopleva, M. & Abbruzzese, J. L.
Antidiabetic therapies affect risk of pancreatic cancer. Gastroenterology
137, 482–488 (2009).
Nielsen, S. F., Nordestgaard, B. G. & Bojesen, S. E.
Statin use and reduced cancer-related mortality. N. Engl. J. Med.
367, 1792–1802 (2012). The results of this large, retrospective clinical study suggest that the use of statins by patients with 13 distinct tumour types is associated with a statistically significant reduction in cancer-related mortality.
Poynter, J. N.
et al. Statins and the risk of colorectal cancer. N. Engl. J. Med.
352, 2184–2192 (2005).
Appleyard, M. V.
et al. Phenformin as prophylaxis and therapy in breast cancer xenografts. Br. J. Cancer
106, 1117–1122 (2012).
Anisimov, V. N.
et al. Central and peripheral effects of insulin/IGF-1 signaling in aging and cancer: antidiabetic drugs as geroprotectors and anticarcinogens. Ann. NY Acad. Sci.
1057, 220–234 (2005).
Shackelford, D. B.
et al. LKB1 inactivation dictates therapeutic response of non-small cell lung cancer to the metabolism drug phenformin. Cancer Cell
23, 143–158 (2013).
Garber, A. J.
Metformin: mechanisms of antihyperglycemic action, other pharmacodynamic properties, and safety perspectives. Endocr. Pract. Endocrinol.
3, 359–370 (1997).
Golomb, B. A. & Evans, M. A.
Statin adverse effects: a review of the literature and evidence for a mitochondrial mechanism. Am. J. Cardiovasc. Drugs
8, 373–418 (2008).
et al. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J. Clin. Invest.
120, 2355–2369 (2010).
Bowker, S. L., Majumdar, S. R., Veugelers, P. & Johnson, J. A.
Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care
29, 254–258 (2006).
Hirsch, H. A., Iliopoulos, D. & Struhl, K.
Metformin inhibits the inflammatory response associated with cellular transformation and cancer stem cell growth. Proc. Natl Acad. Sci. USA
110, 972–977 (2013).
et al. Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res.
67, 6745–6752 (2007).
Hirsch, H. A., Iliopoulos, D., Tsichlis, P. N. & Struhl, K.
Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res.
69, 7507–7511 (2009).
Fendt, S. M.
et al. Metformin decreases glucose oxidation and increases the dependency of prostate cancer cells on reductive glutamine metabolism. Cancer Res.
73, 4429–4438 (2013).
Zhuang, L., Kim, J., Adam, R. M., Solomon, K. R. & Freeman, M. R.
Cholesterol targeting alters lipid raft composition and cell survival in prostate cancer cells and xenografts. J. Clin. Invest.
115, 959–968 (2005).
Ma, L., Niknejad, N., Gorn-Hondermann, I., Dayekh, K. & Dimitroulakos, J.
Lovastatin induces multiple stress pathways including LKB1/AMPK activation that regulate its cytotoxic effects in squamous cell carcinoma cells. PloS ONE
7, e46055 (2012).
Bonovas, S., Nikolopoulos, G. K. & Bagos, P. G.
Use of fibrates and cancer risk: a systematic review and meta-analysis of 17 long-term randomized placebo-controlled trials. PloS ONE
7, e45259 (2012).
Carracedo, A., Cantley, L. C. & Pandolfi, P. P.
Cancer metabolism: fatty acid oxidation in the limelight. Nature Rev. Cancer
13, 227–232 (2013).
Lee, C. & Longo, V. D.
Fasting versus dietary restriction in cellular protection and cancer treatment: from model organisms to patients. Oncogene
30, 3305–3316 (2011).
Poff, A. M., Ari, C., Seyfried, T. N. & D'Agostino, D. P.
The ketogenic diet and hyperbaric oxygen therapy prolong survival in mice with systemic metastatic cancer. PloS ONE
8, e65522 (2013).
et al. Fasting cycles retard growth of tumors and sensitize a range of cancer cell types to chemotherapy. Sci. Transl. Med.
4, 124ra127 (2012). This study suggested that several cycles of organismal fasting specifically sensitize malignant cells to the antineoplastic effects of several chemotherapeutics.
Cancer research. Can fasting blunt chemotherapy's debilitating side effects?
321, 1146–1147 (2008).
et al. Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival. Cell
142, 531–543 (2010).
Kalaany, N. Y. & Sabatini, D. M.
Tumours with PI3K activation are resistant to dietary restriction. Nature
458, 725–731 (2009).
et al. Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N. Engl. J. Med.
367, 1596–1606 (2012).
Sandler, R. S.
et al. A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer. N. Engl. J. Med.
348, 883–890 (2003).
Chan, A. T., Ogino, S. & Fuchs, C. S.
Aspirin and the risk of colorectal cancer in relation to the expression of COX-2. N. Engl. J. Med.
356, 2131–2142 (2007).
et al. Aspirin use and risk of colorectal cancer according to BRAF mutation status. JAMA
309, 2563–2571 (2013).
Hawley, S. A.
et al. The ancient drug salicylate directly activates AMP-activated protein kinase. Science
336, 918–922 (2012).
Cairns, R. A., Harris, I. S. & Mak, T. W.
Regulation of cancer cell metabolism. Nature Rev. Cancer
11, 85–95 (2011).
Levine, A. J. & Puzio-Kuter, A. M.
The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes. Science
330, 1340–1344 (2010).
Isaacs, J. S.
et al. HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. Cancer Cell
8, 143–153 (2005).
Selak, M. A.
et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-α prolyl hydroxylase. Cancer Cell
7, 77–85 (2005).
et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature
462, 739–744 (2009). This paper was the first to demonstrate that cancer-associated variants of IDH1 are characterized by a neomorphic enzymatic activity, hence driving the accumulation of the oncometabolite 2-HG.
Dang, C. V., Le, A. & Gao, P.
MYC-induced cancer cell energy metabolism and therapeutic opportunities. Clin. Cancer Res.
15, 6479–6483 (2009).
David, C. J., Chen, M., Assanah, M., Canoll, P. & Manley, J. L.
HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer. Nature
463, 364–368 (2010).
Wise, D. R.
et al. Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc. Natl Acad. Sci. USA
105, 18782–18787 (2008).
et al. c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature
458, 762–765 (2009).
et al. Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells. Science
325, 1555–1559 (2009).
et al. Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell
149, 656–670 (2012).
Engelman, J. A.
Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nature Rev. Cancer
9, 550–562 (2009).
Engelman, J. A.
et al. Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nature Med.
14, 1351–1356 (2008).
et al. Regulation of GLUT1 gene transcription by the serine/threonine kinase Akt1. J. Biol. Chem.
274, 20281–20286 (1999).
Samih, N., Hovsepian, S., Aouani, A., Lombardo, D. & Fayet, G.
Glut-1 translocation in FRTL-5 thyroid cells: role of phosphatidylinositol 3-kinase and N-glycosylation. Endocrinology
141, 4146–4155 (2000).
Clarke, J. F., Young, P. W., Yonezawa, K., Kasuga, M. & Holman, G. D.
Inhibition of the translocation of GLUT1 and GLUT4 in 3T3-L1 cells by the phosphatidylinositol 3-kinase inhibitor, wortmannin. Biochem. J.
300, 631–635 (1994).
et al. Hexokinase-mitochondria interaction mediated by Akt is required to inhibit apoptosis in the presence or absence of Bax and Bak. Mol. Cell
16, 819–830 (2004).
Deprez, J., Vertommen, D., Alessi, D. R., Hue, L. & Rider, M. H.
Phosphorylation and activation of heart 6-phosphofructo-2-kinase by protein kinase B and other protein kinases of the insulin signaling cascades. J. Biol. Chem.
272, 17269–17275 (1997).
et al. The ER UDPase ENTPD5 promotes protein N-glycosylation, the Warburg effect, and proliferation in the PTEN pathway. Cell
143, 711–724 (2010).
Berwick, D. C., Hers, I., Heesom, K. J., Moule, S. K. & Tavare, J. M.
The identification of ATP-citrate lyase as a protein kinase B (Akt) substrate in primary adipocytes. J. Biol. Chem.
277, 33895–33900 (2002).
Wang, R. C.
et al. Akt-mediated regulation of autophagy and tumorigenesis through Beclin 1 phosphorylation. Science
338, 956–959 (2012).
Yue, Z., Jin, S., Yang, C., Levine, A. J. & Heintz, N.
Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc. Natl Acad. Sci. USA
100, 15077–15082 (2003).
et al. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol. Cell
39, 171–183 (2010).
Robitaille, A. M.
et al. Quantitative phosphoproteomics reveal mTORC1 activates de novo pyrimidine synthesis. Science
339, 1320–1323 (2013).
Ben-Sahra, I., Howell, J. J., Asara, J. M. & Manning, B. D.
Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1. Science
339, 1323–1328 (2013).
Laplante, M. & Sabatini, D. M.
mTOR signaling in growth control and disease. Cell
149, 274–293 (2012).
et al. The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4. Cell
153, 840–854 (2013).
Ran, C., Liu, H., Hitoshi, Y. & Israel, M. A.
Proliferation-independent control of tumor glycolysis by PDGFR-mediated AKT activation. Cancer Res.
73, 1831–1843 (2013).
Zhao, Y. H.
et al. Upregulation of lactate dehydrogenase A by ErbB2 through heat shock factor 1 promotes breast cancer cell glycolysis and growth. Oncogene
28, 3689–3701 (2009).
Youle, R. J. & Strasser, A.
The BCL-2 protein family: opposing activities that mediate cell death. Nature Rev. Mol. Cell Biol.
9, 47–59 (2008).
Rong, Y. & Distelhorst, C. W.
Bcl-2 protein family members: versatile regulators of calcium signaling in cell survival and apoptosis. Annu. Rev. Physiol.
70, 73–91 (2008).
Alavian, K. N.
et al. Bcl-xL regulates metabolic efficiency of neurons through interaction with the mitochondrial F1FO ATP synthase. Nature Cell Biol.
13, 1224–1233 (2011).
Perciavalle, R. M.
et al. Anti-apoptotic MCL-1 localizes to the mitochondrial matrix and couples mitochondrial fusion to respiration. Nature Cell Biol.
14, 575–583 (2012). The studies in references 75 and 76 reported that two distinct anti-apoptotic members of the BCL-2 protein family can physically interact with — and hence regulate the enzymatic activity of — the mitochondrial ATP synthase.
Perkins, N. D.
The diverse and complex roles of NF-κB subunits in cancer. Nature Rev. Cancer
12, 121–132 (2012).
Kawauchi, K., Araki, K., Tobiume, K. & Tanaka, N.
p53 regulates glucose metabolism through an IKK-NF-κB pathway and inhibits cell transformation. Nature Cell Biol.
10, 611–618 (2008).
Watanabe, M., Abe, N., Oshikiri, Y., Stanbridge, E. J. & Kitagawa, T.
Selective growth inhibition by glycogen synthase kinase-3 inhibitors in tumorigenic HeLa hybrid cells is mediated through NF-κB-dependent GLUT3 expression. Oncogenesis
1, e21 (2012).
et al. NF-κB controls energy homeostasis and metabolic adaptation by upregulating mitochondrial respiration. Nature Cell Biol.
13, 1272–1279 (2011).
Schwartzenberg-Bar-Yoseph, F., Armoni, M. & Karnieli, E.
The tumor suppressor p53 down-regulates glucose transporters GLUT1 and GLUT4 gene expression. Cancer Res.
64, 2627–2633 (2004).
et al. TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell
126, 107–120 (2006).
et al. Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function. Proc. Natl Acad. Sci. USA
107, 7455–7460 (2010).
et al. p53 regulates mitochondrial respiration. Science
312, 1650–1653 (2006).
Maiuri, M. C.
et al. Autophagy regulation by p53. Curr. Opin. Cell Biol.
22, 181–185 (2010).
et al. p53 regulates biosynthesis through direct inactivation of glucose-6-phosphate dehydrogenase. Nature Cell Biol.
13, 310–316 (2011).
et al. p53 inhibits autophagy by interacting with the human ortholog of yeast Atg17, RB1CC1/FIP200. Cell Cycle
10, 2763–2769 (2011).
Vousden, K. H. & Ryan, K. M.
p53 and metabolism. Nature Rev. Cancer
9, 691–700 (2009).
Reid, M. A.
et al. The B55α subunit of PP2A drives a p53-dependent metabolic adaptation to glutamine deprivation. Mol. Cell
50, 200–211 (2013).
Maddocks, O. D.
et al. Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells. Nature
493, 542–546 (2013). The studies in references 89 and 90 show that p53 is involved in cytoprotective signal transduction pathways activated by glutamine or serine deprivation, which suggests that p53-deficient malignant cells may be particularly sensitive to chemicals that limit the bioavailability of these amino acids.
Denko, N. C.
Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nature Rev. Cancer
8, 705–713 (2008).
Kaelin, W. G. Jr.
The von Hippel-Lindau tumour suppressor protein: O2 sensing and cancer. Nature Rev. Cancer
8, 865–873 (2008).
Song, M. S., Salmena, L. & Pandolfi, P. P.
The functions and regulation of the PTEN tumour suppressor. Nature Rev. Mol. Cell Biol.
13, 283–296 (2012).
et al. Loss of PTEN facilitates HIF-1-mediated gene expression. Genes Dev.
14, 391–396 (2000).
et al. Requirement for ribosomal protein S6 kinase 1 to mediate glycolysis and apoptosis resistance induced by Pten deficiency. Proc. Natl Acad. Sci. USA
108, 2361–2365 (2011).
et al. Systemic elevation of PTEN induces a tumor-suppressive metabolic state. Cell
149, 49–62 (2012).
et al. Pten positively regulates brown adipose function, energy expenditure, and longevity. Cell. Metab.
15, 382–394 (2012).
Shackelford, D. B. & Shaw, R. J.
The LKB1–AMPK pathway: metabolism and growth control in tumour suppression. Nature Rev. Cancer
9, 563–575 (2009).
Hardie, D. G., Ross, F. A. & Hawley, S. A.
AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nature Rev. Mol. Cell Biol.
13, 251–262 (2012).
Shiloh, Y. & Ziv, Y.
The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. Nature Rev. Mol. Cell Biol.
14, 197–210 (2013).
et al. Loss of ATM positively regulates the expression of hypoxia inducible factor 1 (HIF-1) through oxidative stress: role in the physiopathology of the disease. Cell Cycle
9, 2814–2822 (2010).
Cam, H., Easton, J. B., High, A. & Houghton, P. J.
mTORC1 signaling under hypoxic conditions is controlled by ATM-dependent phosphorylation of HIF-1α. Mol. Cell
40, 509–520 (2010).
Wilson, W. R. & Hay, M. P.
Targeting hypoxia in cancer therapy. Nature Rev. Cancer
11, 393–410 (2011).
Bialik, S. & Kimchi, A.
Lethal weapons: DAP-kinase, autophagy and cell death: DAP-kinase regulates autophagy. Curr. Opin. Cell Biol.
22, 199–205 (2010).
Mor, I., Carlessi, R., Ast, T., Feinstein, E. & Kimchi, A.
Death-associated protein kinase increases glycolytic rate through binding and activation of pyruvate kinase. Oncogene
31, 683–693 (2012).
et al. Tyrosine phosphorylation inhibits PKM2 to promote the Warburg effect and tumor growth. Sci. Signal.
2, ra73 (2009).
Christofk, H. R., Vander Heiden, M. G., Wu, N., Asara, J. M. & Cantley, L. C.
Pyruvate kinase M2 is a phosphotyrosine-binding protein. Nature
452, 181–186 (2008).
Christofk, H. R.
et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature
452, 230–233 (2008).
et al. Acetylation targets the M2 isoform of pyruvate kinase for degradation through chaperone-mediated autophagy and promotes tumor growth. Mol. Cell
42, 719–730 (2011).
et al. Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to cellular antioxidant responses. Science
334, 1278–1283 (2011).
et al. The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1α. Cell
140, 280–293 (2010).
et al. The histone deacetylase SIRT6 is a tumor suppressor that controls cancer metabolism. Cell
151, 1185–1199 (2012).
Kaidi, A., Weinert, B. T., Choudhary, C. & Jackson, S. P.
Human SIRT6 promotes DNA end resection through CtIP deacetylation. Science
329, 1348–1353 (2010).
et al. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell
124, 315–329 (2006).
et al. Liver cancer initiation is controlled by AP-1 through SIRT6-dependent inhibition of survivin. Nature Cell Biol.
14, 1203–1211 (2012).
Altieri, D. C.
Survivin, cancer networks and pathway-directed drug discovery. Nature Rev. Cancer
8, 61–70 (2008).
Houtkooper, R. H., Pirinen, E. & Auwerx, J.
Sirtuins as regulators of metabolism and healthspan. Nature Rev. Mol. Cell Biol.
13, 225–238 (2012).
Saunders, L. R. & Verdin, E.
Sirtuins: critical regulators at the crossroads between cancer and aging. Oncogene
26, 5489–5504 (2007).
Bell, E. L., Emerling, B. M., Ricoult, S. J. & Guarente, L.
SirT3 suppresses hypoxia inducible factor 1α and tumor growth by inhibiting mitochondrial ROS production. Oncogene
30, 2986–2996 (2011).
Haigis, M. C., Deng, C. X., Finley, L. W., Kim, H. S. & Gius, D.
SIRT3 is a mitochondrial tumor suppressor: a scientific tale that connects aberrant cellular ROS, the Warburg effect, and carcinogenesis. Cancer Res.
72, 2468–2472 (2012).
Chipuk, J. E.
et al. Sphingolipid metabolism cooperates with BAK and BAX to promote the mitochondrial pathway of apoptosis. Cell
148, 988–1000 (2012).
et al. Loss of the tumor suppressor PML in human cancers of multiple histologic origins. J. Natl Cancer Inst.
96, 269–279 (2004).
et al. A metabolic prosurvival role for PML in breast cancer. J. Clin. Invest.
122, 3088–3100 (2012).
et al. PPARδ induces estrogen receptor-positive mammary neoplasia through an inflammatory and metabolic phenotype linked to mTOR activation. Cancer Res.
73, 4349–4361 (2013).
et al. A PML–PPAR-δ pathway for fatty acid oxidation regulates hematopoietic stem cell maintenance. Nature Med.
18, 1350–1358 (2012).
Jeon, S. M., Chandel, N. S. & Hay, N.
AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature
485, 661–665 (2012).
Schafer, Z. T.
et al. Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment. Nature
461, 109–113 (2009).
Gottlieb, E. & Tomlinson, I. P.
Mitochondrial tumour suppressors: a genetic and biochemical update. Nature Rev. Cancer
5, 857–866 (2005).
et al. Renal cyst formation in Fh1-deficient mice is independent of the Hif/Phd pathway: roles for fumarate in KEAP1 succination and Nrf2 signaling. Cancer Cell
20, 524–537 (2011).
et al. SDH mutations establish a hypermethylator phenotype in paraganglioma. Cancer Cell
23, 739–752 (2013).
Owens, K. M.
et al. Genomic instability induced by mutant succinate dehydrogenase subunit D (SDHD) is mediated by O2−• and H2O2. Free Radic. Biol. Med.
52, 160–166 (2012).
et al. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med.
360, 765–773 (2009).
Dang, L., Jin, S. & Su, S. M.
IDH mutations in glioma and acute myeloid leukemia. Trends Mol. Med.
16, 387–397 (2010).
Yang, H., Ye, D., Guan, K. L. & Xiong, Y.
IDH1 and IDH2 mutations in tumorigenesis: mechanistic insights and clinical perspectives. Clin. Cancer Res.
18, 5562–5571 (2012).
Ward, P. S.
et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting α-ketoglutarate to 2-hydroxyglutarate. Cancer Cell
17, 225–234 (2010).
Zhang, W. C.
et al. Glycine decarboxylase activity drives non-small cell lung cancer tumor-initiating cells and tumorigenesis. Cell
148, 259–272 (2012).
et al. Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature
457, 910–914 (2009).
Reitman, Z. J. & Yan, H.
Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterations at a crossroads of cellular metabolism. J. Natl Cancer Inst.
102, 932–941 (2010).
et al. Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1α. Science
324, 261–265 (2009).
et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell
19, 17–30 (2011).
et al. Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation. Nature
483, 484–488 (2012).
Figueroa, M. E.
et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell
18, 553–567 (2010).
et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature
483, 474–478 (2012).
et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature
483, 479–483 (2012).
et al. IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics. Nature
488, 656–659 (2012).
Leonardi, R., Subramanian, C., Jackowski, S. & Rock, C. O.
Cancer-associated isocitrate dehydrogenase mutations inactivate NADPH-dependent reductive carboxylation. J. Biol. Chem.
287, 14615–14620 (2012).
Losman, J. A.
et al. (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Science
339, 1621–1625 (2013).
Metallo, C. M.
et al. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature
481, 380–384 (2012).
Mullen, A. R.
et al. Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature
481, 385–388 (2012). The studies in references 148 and 149 show that IDH1-catalysed reductive carboxylation is the main metabolic pathway used by malignant cells to divert glutamine towards lipogenesis, especially under hypoxic conditions.
Gameiro, P. A.
et al. In vivo HIF-mediated reductive carboxylation is regulated by citrate levels and sensitizes VHL-deficient cells to glutamine deprivation. Cell. Metab.
17, 372–385 (2013).
Fendt, S. M.
et al. Reductive glutamine metabolism is a function of the α-ketoglutarate to citrate ratio in cells. Nature Commun.
4, 2236 (2013).
Opitz, C. A.
et al. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature
478, 197–203 (2011).
et al. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nature Med.
9, 1269–1274 (2003).
Dwarakanath, B. S.
et al. Clinical studies for improving radiotherapy with 2-deoxy-D-glucose: present status and future prospects. J. Cancer Res. Ther.
5 (Suppl. 1), 21–26 (2009).
et al. Hexokinase 2 is a key mediator of aerobic glycolysis and promotes tumor growth in human glioblastoma multiforme. J. Exp. Med.
208, 313–326 (2011).
et al. Methyl jasmonate binds to and detaches mitochondria-bound hexokinase. Oncogene
27, 4636–4643 (2008).
Jae, H. J.
et al. The antitumor effect and hepatotoxicity of a hexokinase II inhibitor 3-bromopyruvate: in vivo investigation of intraarterial administration in a rabbit VX2 hepatoma model. Kor. J. Radiol.
10, 596–603 (2009).
et al. Methyljasmonate displays in vitro and in vivo activity against multiple myeloma cells. Br. J. Haematol.
159, 340–351 (2012).
et al. MCT1-mediated transport of a toxic molecule is an effective strategy for targeting glycolytic tumors. Nature Genet.
45, 104–108 (2013).
Shoshan, M. C.
3-bromopyruvate: targets and outcomes. J. Bioenerg. Biomembr.
44, 7–15 (2012).
Hamanaka, R. B. & Chandel, N. S.
Targeting glucose metabolism for cancer therapy. J. Exp. Med.
209, 211–215 (2012).
et al. Small-molecule inhibition of 6-phosphofructo-2-kinase activity suppresses glycolytic flux and tumor growth. Mol. Cancer Ther.
7, 110–120 (2008).
et al. Ras transformation requires metabolic control by 6-phosphofructo-2-kinase. Oncogene
25, 7225–7234 (2006).
Clem, B. F.
et al. Targeting 6-phosphofructo-2-kinase (PFKFB3) as a therapeutic strategy against cancer. Mol. Cancer Ther.
12, 1461–1470 (2013).
Kumagai, S., Narasaki, R. & Hasumi, K.
Glucose-dependent active ATP depletion by koningic acid kills high-glycolytic cells. Biochem. Biophys. Res. Commun.
365, 362–368 (2008).
Goldberg, M. S. & Sharp, P. A.
Pyruvate kinase M2-specific siRNA induces apoptosis and tumor regression. J. Exp. Med.
209, 217–224 (2012).
et al. c-Myc transactivation of LDH-A: implications for tumor metabolism and growth. Proc. Natl Acad. Sci. USA
94, 6658–6663 (1997).
et al. Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression. Proc. Natl Acad. Sci. USA
107, 2037–2042 (2010).
Gautier, E. L.
et al. HDL and Glut1 inhibition reverse a hypermetabolic state in mouse models of myeloproliferative disorders. J. Exp. Med.
210, 339–353 (2013).
et al. A small-molecule inhibitor of glucose transporter 1 downregulates glycolysis, induces cell-cycle arrest, and inhibits cancer cell growth in vitro and in vivo. Mol. Cancer Ther.
11, 1672–1682 (2012).
Zhan, T., Digel, M., Kuch, E. M., Stremmel, W. & Fullekrug, J.
Silybin and dehydrosilybin decrease glucose uptake by inhibiting GLUT proteins. J. Cell. Biochem.
112, 849–859 (2011).
et al. CD147 silencing inhibits lactate transport and reduces malignant potential of pancreatic cancer cells in in vivo and in vitro models. Gut
58, 1391–1398 (2009).
et al. In vitro and in vivo prostate cancer metastasis and chemoresistance can be modulated by expression of either CD44 or CD147. PloS ONE
7, e40716 (2012).
De Bock, K.
et al. Role of PFKFB3-driven glycolysis in vessel sprouting. Cell
154, 651–663 (2013).
et al. Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis. Nature Chem. Biol.
8, 839–847 (2012).
et al. Small molecule activation of PKM2 in cancer cells induces serine auxotrophy. Chem. Biol.
19, 1187–1198 (2012).
et al. M2 isoform of pyruvate kinase is dispensable for tumor maintenance and growth. Proc. Natl Acad. Sci. USA
110, 489–494 (2013).
Israelsen, W. J.
et al. PKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells. Cell (in the press).
Michelakis, E. D., Webster, L. & Mackey, J. R.
Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer. Br. J. Cancer
99, 989–994 (2008).
et al. Tyrosine phosphorylation of mitochondrial pyruvate dehydrogenase kinase 1 is important for cancer metabolism. Mol. Cell
44, 864–877 (2011).
Papandreou, I., Cairns, R. A., Fontana, L., Lim, A. L. & Denko, N. C.
HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell. Metab.
3, 187–197 (2006).
Kim, J. W., Tchernyshyov, I., Semenza, G. L. & Dang, C. V.
HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell. Metab.
3, 177–185 (2006).
et al. A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell
11, 37–51 (2007).
Shen, Y. C.
et al. Activating oxidative phosphorylation by a pyruvate dehydrogenase kinase inhibitor overcomes sorafenib resistance of hepatocellular carcinoma. Br. J. Cancer
108, 72–81 (2013).
Kumar, A., Kant, S. & Singh, S. M.
Novel molecular mechanisms of antitumor action of dichloroacetate against T cell lymphoma: implication of altered glucose metabolism, pH homeostasis and cell survival regulation. Chem. Biol. Interact.
199, 29–37 (2012).
et al. Acidity generated by the tumor microenvironment drives local invasion. Cancer Res.
73, 1524–1535 (2013).
et al. Modulation of microenvironment acidity reverses anergy in human and murine tumor-infiltrating T lymphocytes. Cancer Res.
72, 2746–2756 (2012).
Michelakis, E. D.
et al. Metabolic modulation of glioblastoma with dichloroacetate. Sci. Transl. Med.
2, 31ra34 (2010). This study reports that DCA is well tolerated by patients with glioblastoma and it can induce functional alterations in the mitochondria of malignant cells, thus confirming the existence of a therapeutic window for the use of metabolic inhibitors in at least a subset of patients with cancer.
Strum, S. B.
et al. Case report: sodium dichloroacetate (DCA) inhibition of the “Warburg Effect” in a human cancer patient: complete response in non-Hodgkin's lymphoma after disease progression with rituximab-CHOP. J. Bioenerg. Biomembr.
45, 307–315 (2013).
Neri, D. & Supuran, C. T.
Interfering with pH regulation in tumours as a therapeutic strategy. Nature Rev. Drug Discov.
10, 767–777 (2011).
Haddad, R. I.
et al. A phase II clinical and pharmacodynamic study of E7070 in patients with metastatic, recurrent, or refractory squamous cell carcinoma of the head and neck: modulation of retinoblastoma protein phosphorylation by a novel chloroindolyl sulfonamide cell cycle inhibitor. Clin. Cancer Res.
10, 4680–4687 (2004).
Smyth, J. F.
et al. Phase II study of E7070 in patients with metastatic melanoma. Ann. Oncol.
16, 158–161 (2005).
Talbot, D. C.
et al. A randomized phase II pharmacokinetic and pharmacodynamic study of indisulam as second-line therapy in patients with advanced non-small cell lung cancer. Clin. Cancer Res.
13, 1816–1822 (2007).
Wallace, D. C.
Mitochondria and cancer. Nature Rev. Cancer
12, 685–698 (2012).
Santidrian, A. F.
et al. Mitochondrial complex I activity and NAD+/NADH balance regulate breast cancer progression. J. Clin. Invest.
123, 1068–1081 (2013).
Sharma, L. K.
et al. Mitochondrial respiratory complex I dysfunction promotes tumorigenesis through ROS alteration and AKT activation. Hum. Mol. Genet.
20, 4605–4616 (2011).
DeBerardinis, R. J.
et al. Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc. Natl Acad. Sci. USA
104, 19345–19350 (2007).
Wise, D. R. & Thompson, C. B.
Glutamine addiction: a new therapeutic target in cancer. Trends Biochem. Sci.
35, 427–433 (2010).
Fulda, S., Galluzzi, L. & Kroemer, G.
Targeting mitochondria for cancer therapy. Nature Rev. Drug Discov.
9, 447–464 (2010).
El-Mir, M. Y.
et al. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J. Biol. Chem.
275, 223–228 (2000).
Shaw, R. J.
et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science
310, 1642–1646 (2005).
et al. Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J. Clin. Invest.
118, 3930–3942 (2008).
et al. Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science
340, 622–626 (2013).
et al. An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science
340, 626–630 (2013). The studies in references 203 and 204 were the first to demonstrate that small chemicals that specifically target cancer-associated IDH1 and IDH2 variants can limit the proliferation and induce the differentiation of glioma and leukaemia cells.
Wang, J. B.
et al. Targeting mitochondrial glutaminase activity inhibits oncogenic transformation. Cancer Cell
18, 207–219 (2010).
Seltzer, M. J.
et al. Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1. Cancer Res.
70, 8981–8987 (2010).
et al. Glioblastoma cells require glutamate dehydrogenase to survive impairments of glucose metabolism or Akt signaling. Cancer Res.
69, 7986–7993 (2009).
et al. Pyruvate carboxylase is required for glutamine-independent growth of tumor cells. Proc. Natl Acad. Sci. USA
108, 8674–8679 (2011).
Enns, G. M.
et al. Survival after treatment with phenylacetate and benzoate for urea-cycle disorders. N. Engl. J. Med.
356, 2282–2292 (2007).
Chang, S. M.
et al. Phase II study of phenylacetate in patients with recurrent malignant glioma: a North American Brain Tumor Consortium report. J. Clin. Oncol.
17, 984–990 (1999).
Camacho, L. H.
et al. Phase I dose escalation clinical trial of phenylbutyrate sodium administered twice daily to patients with advanced solid tumors. Investigat. Drugs
25, 131–138 (2007).
Carducci, M. A.
et al. A Phase I clinical and pharmacological evaluation of sodium phenylbutyrate on an 120-h infusion schedule. Clin. Cancer Res.
7, 3047–3055 (2001).
Pike, L. S., Smift, A. L., Croteau, N. J., Ferrick, D. A. & Wu, M.
Inhibition of fatty acid oxidation by etomoxir impairs NADPH production and increases reactive oxygen species resulting in ATP depletion and cell death in human glioblastoma cells. Biochim. Biophys. Acta
1807, 726–734 (2011).
et al. Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction. J. Clin. Invest.
120, 142–156 (2010).
et al. Carnitine palmitoyltransferase 1C promotes cell survival and tumor growth under conditions of metabolic stress. Genes Dev.
25, 1041–1051 (2011).
Holubarsch, C. J.
et al. A double-blind randomized multicentre clinical trial to evaluate the efficacy and safety of two doses of etomoxir in comparison with placebo in patients with moderate congestive heart failure: the ERGO (etomoxir for the recovery of glucose oxidation) study. Clin. Sci.
113, 205–212 (2007).
Kantor, P. F., Lucien, A., Kozak, R. & Lopaschuk, G. D.
The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. Circ. Res.
86, 580–588 (2000).
Andela, V. B., Altuwaijri, S., Wood, J. & Rosier, R. N.
Inhibition of β-oxidative respiration is a therapeutic window associated with the cancer chemo-preventive activity of PPARγ agonists. FEBS Lett.
579, 1765–1769 (2005).
Suckow, M. A.
et al. The anti-ischemia agent ranolazine promotes the development of intestinal tumors in APC(Min/+) mice. Cancer Lett.
209, 165–169 (2004).
Kuo, W., Lin, J. & Tang, T. K.
Human glucose-6-phosphate dehydrogenase (G6PD) gene transforms NIH 3T3 cells and induces tumors in nude mice. Int. J. Cancer
85, 857–864 (2000).
et al. Silencing of TKTL1 by siRNA inhibits proliferation of human gastric cancer cells in vitro and in vivo. Cancer Biol. Ther.
9, 710–716 (2010).
et al. Phosphoglycerate mutase 1 coordinates glycolysis and biosynthesis to promote tumor growth. Cancer Cell
22, 585–600 (2012).
Howes, R. E., Battle, K. E., Satyagraha, A. W., Baird, J. K. & Hay, S. I.
G6PD deficiency: global distribution, genetic variants and primaquine therapy. Adv. Parasitol.
81, 133–201 (2013).
Pisano, M., Cocco, P., Cherchi, R., Onnis, R. & Cherchi, P.
Glucose-6-phosphate dehydrogenase deficiency and lung cancer: a hospital based case-control study. Tumori
77, 12–15 (1991).
Cocco, P., Dessi, S., Avataneo, G., Picchiri, G. & Heinemann, E.
Glucose-6-phosphate dehydrogenase deficiency and cancer in a Sardinian male population: a case-control study. Carcinogenesis
10, 813–816 (1989).
et al. Serine is a natural ligand and allosteric activator of pyruvate kinase M2. Nature
491, 458–462 (2012).
Keller, K. E., Tan, I. S. & Lee, Y. S.
SAICAR stimulates pyruvate kinase isoform M2 and promotes cancer cell survival in glucose-limited conditions. Science
338, 1069–1072 (2012). The studies in references 226 and 227 showed that serine and SAICAR operate as endogenous allosteric activators of PKM2, de facto adjusting the glycolytic flux on the anabolic demand of malignant cells.
et al. Pyruvate kinase M2 promotes de novo serine synthesis to sustain mTORC1 activity and cell proliferation. Proc. Natl Acad. Sci. USA
109, 6904–6909 (2012).
Locasale, J. W.
et al. Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nature Genet.
43, 869–874 (2011).
et al. Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature
476, 346–350 (2011).
Broome, J. D.
Studies on the mechanism of tumor inhibition by L-asparaginase. Effects of the enzyme on asparagine levels in the blood, normal tissues, and 6C3HED lymphomas of mice: differences in asparagine formation and utilization in asparaginase-sensitive and -resistant lymphoma cells. J. Exp. Med.
127, 1055–1072 (1968).
Bach, S. J. & Swaine, D.
The effect of arginase on the retardation of tumour growth. Br. J. Cancer
19, 379–386 (1965).
et al. Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation. Science
336, 1040–1044 (2012). Using an extensive metabolomic profiling approach, the authors of this study identified a crucial role for glycine in the elevated proliferation rate of malignant cells.
Muller, H. J. & Boos, J.
Use of L-asparaginase in childhood ALL. Crit. Rev. Oncol. Hematol.
28, 97–113 (1998).
Ott, P. A.
et al. Phase I/II study of pegylated arginine deiminase (ADI-PEG 20) in patients with advanced melanoma. Invest. New Drugs
31, 425–434 (2013).
Yang, T. S.
et al. A randomised phase II study of pegylated arginine deiminase (ADI-PEG 20) in Asian advanced hepatocellular carcinoma patients. Br. J. Cancer
103, 954–960 (2010).
Sabatini, D. M.
mTOR and cancer: insights into a complex relationship. Nature Rev. Cancer
6, 729–734 (2006).
Benjamin, D., Colombi, M., Moroni, C. & Hall, M. N.
Rapamycin passes the torch: a new generation of mTOR inhibitors. Nature Rev. Drug Discov.
10, 868–880 (2011).
et al. Metabolic profiling of hypoxic cells revealed a catabolic signature required for cell survival. PloS ONE
6, e24411 (2011).
Menendez, J. A. & Lupu, R.
Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nature Rev. Cancer
7, 763–777 (2007).
Alli, P. M., Pinn, M. L., Jaffee, E. M., McFadden, J. M. & Kuhajda, F. P.
Fatty acid synthase inhibitors are chemopreventive for mammary cancer in neu-N transgenic mice. Oncogene
24, 39–46 (2005).
et al. The fatty acid synthase inhibitor orlistat reduces experimental metastases and angiogenesis in B16-F10 melanomas. Br. J. Cancer
107, 977–987 (2012).
et al. ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell
8, 311–321 (2005).
et al. Chemical inhibition of acetyl-CoA carboxylase induces growth arrest and cytotoxicity selectively in cancer cells. Cancer Res.
67, 8180–8187 (2007).
Clem, B. F.
et al. A novel small molecule antagonist of choline kinase-alpha that simultaneously suppresses MAPK and PI3K/AKT signaling. Oncogene
30, 3370–3380 (2011).
et al. Selective inhibition of choline kinase simultaneously attenuates MAPK and PI3K/AKT signaling. Oncogene
29, 139–149 (2010).
Nomura, D. K.
et al. Monoacylglycerol lipase regulates a fatty acid network that promotes cancer pathogenesis. Cell
140, 49–61 (2010).
et al. MYC phosphorylation, activation, and tumorigenic potential in hepatocellular carcinoma are regulated by HMG-CoA reductase. Cancer Res.
71, 2286–2297 (2011).
Kridel, S. J., Axelrod, F., Rozenkrantz, N. & Smith, J. W.
Orlistat is a novel inhibitor of fatty acid synthase with antitumor activity. Cancer Res.
64, 2070–2075 (2004).
Ghosh-Choudhury, N., Mandal, C. C., Ghosh-Choudhury, N. & Ghosh Choudhury, G.
Simvastatin induces derepression of PTEN expression via NFκB to inhibit breast cancer cell growth. Cell. Signal.
22, 749–758 (2010).
et al. Synthetic lethality of PARP and NAMPT inhibition in triple-negative breast cancer cells. EMBO Mol. Med.
4, 1087–1096 (2012).
Okumura, S., Sasaki, T., Minami, Y. & Ohsaki, Y.
Nicotinamide phosphoribosyltransferase: a potent therapeutic target in non-small cell lung cancer with epidermal growth factor receptor-gene mutation. J. Thorac. Oncol.
7, 49–56 (2012).
Holen, K., Saltz, L. B., Hollywood, E., Burk, K. & Hanauske, A. R.
The pharmacokinetics, toxicities, and biologic effects of FK866, a nicotinamide adenine dinucleotide biosynthesis inhibitor. Invest. New Drugs
26, 45–51 (2008).
et al. Results from a phase I, dose-escalation study of PX-478, an orally available inhibitor of HIF-1α. J. Clin. Oncol.
18, Abstr. 3076 (2010).
Sheen, J. H., Zoncu, R., Kim, D. & Sabatini, D. M.
Defective regulation of autophagy upon leucine deprivation reveals a targetable liability of human melanoma cells in vitro and in vivo. Cancer Cell
19, 613–628 (2011).
et al. Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death Differ.
19, 107–120 (2012).
Green, D. R., Galluzzi, L. & Kroemer, G.
Mitochondria and the autophagy-inflammation-cell death axis in organismal aging. Science
333, 1109–1112 (2011).
Ma, Y., Galluzzi, L., Zitvogel, L. & Kroemer, G.
Autophagy and cellular immune responses. Immunity
39, 211–227 (2013).
Wellen, K. E. & Thompson, C. B.
A two-way street: reciprocal regulation of metabolism and signalling. Nature Rev. Mol. Cell Biol.
13, 270–276 (2012). This article provides compelling arguments in support of the notion that metabolism and signal transduction do not constitute entirely separated entities but are instead intimately interconnected and hence cannot be discriminated from each other.
Luo, J., Solimini, N. L. & Elledge, S. J.
Principles of cancer therapy: oncogene and non-oncogene addiction. Cell
136, 823–837 (2009).
et al. Selective killing of cancer cells by a small molecule targeting the stress response to ROS. Nature
475, 231–234 (2011).
et al. Tumor suppression in the absence of p53-mediated cell-cycle arrest, apoptosis, and senescence. Cell
149, 1269–1283 (2012). This is the first paper to demonstrate that p53 can mediate oncosuppressive functions even in conditions in which it cannot trigger cell cycle blockade, senescence or apoptosis.
et al. Non-cell-autonomous tumor suppression by p53. Cell
153, 449–460 (2013).
Locasale, J. W. & Cantley, L. C.
Metabolic flux and the regulation of mammalian cell growth. Cell. Metab.
14, 443–451 (2011).
Galluzzi, L., Kepp, O. & Kroemer, G.
Mitochondria: master regulators of danger signalling. Nature Rev. Mol. Cell Biol.
13, 780–788 (2012).
Galluzzi, L., Kepp, O., Trojel-Hansen, C. & Kroemer, G.
Non-apoptotic functions of apoptosis-regulatory proteins. EMBO Rep.
13, 322–330 (2012).
Gao, X., Wang, H., Yang, J. J., Liu, X. & Liu, Z. R.
Pyruvate kinase M2 regulates gene transcription by acting as a protein kinase. Mol. Cell
45, 598–609 (2012).
et al. Nuclear PKM2 regulates β-catenin transactivation upon EGFR activation. Nature
480, 118–122 (2011).
et al. Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell
145, 732–744 (2011).
Lunt, S. Y. & Vander Heiden, M. G.
Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. Annu. Rev. Cell Dev. Biol.
27, 441–464 (2011).
Fritz, V. & Fajas, L.
Metabolism and proliferation share common regulatory pathways in cancer cells. Oncogene
29, 4369–4377 (2010).
Freed-Pastor, W. A.
et al. Mutant p53 disrupts mammary tissue architecture via the mevalonate pathway. Cell
148, 244–258 (2012).
Munoz-Pinedo, C., El Mjiyad, N. & Ricci, J. E.
Cancer metabolism: current perspectives and future directions. Cell Death Dis.
3, e248 (2012).
Michalek, R. D. & Rathmell, J. C.
The metabolic life and times of a T-cell. Immunol. Rev.
236, 190–202 (2010).
Altman, B. J. & Dang, C. V.
Normal and cancer cell metabolism: lymphocytes and lymphoma. FEBS J.
279, 2598–2609 (2012).
Yuneva, M. O.
et al. The metabolic profile of tumors depends on both the responsible genetic lesion and tissue type. Cell. Metab.
15, 157–170 (2012). This study formally demonstrated that the metabolic profile of neoplastic cells depends not only on their genetic background but also on the tissue in which they develop.
Pietras, K. & Ostman, A.
Hallmarks of cancer: interactions with the tumor stroma. Exp. Cell Res.
316, 1324–1331 (2010).
Nagaraj, S. & Gabrilovich, D. I.
Myeloid-derived suppressor cells in human cancer. Cancer J.
16, 348–353 (2010).
Nieman, K. M.
et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nature Med.
17, 1498–1503 (2011). This study was the first to propose that normal adipocytes stimulate tumour progression not only as they release cytokines but also as they directly transfer fatty acid to malignant cells, thus boosting their proliferation.
et al. Evidence for a stromal-epithelial “lactate shuttle” in human tumors: MCT4 is a marker of oxidative stress in cancer-associated fibroblasts. Cell Cycle
10, 1772–1783 (2011).
Martinez-Outschoorn, U. E.
et al. Cancer cells metabolically “fertilize” the tumor microenvironment with hydrogen peroxide, driving the Warburg effect: implications for PET imaging of human tumors. Cell Cycle
10, 2504–2520 (2011).
Kasischke, K. A., Vishwasrao, H. D., Fisher, P. J., Zipfel, W. R. & Webb, W. W.
Neural activity triggers neuronal oxidative metabolism followed by astrocytic glycolysis. Science
305, 99–103 (2004).
et al. Pyruvate kinase expression (PKM1 and PKM2) in cancer-associated fibroblasts drives stromal nutrient production and tumor growth. Cancer Biol. Ther.
12, 1101–1113 (2011).
et al. Understanding the Warburg effect and the prognostic value of stromal caveolin-1 as a marker of a lethal tumor microenvironment. Breast Cancer Res.
13, 213 (2011).
Dai, C., Whitesell, L., Rogers, A. B. & Lindquist, S.
Heat shock factor 1 is a powerful multifaceted modifier of carcinogenesis. Cell
130, 1005–1018 (2007).
Vander Heiden, M. G.
et al. Identification of small molecule inhibitors of pyruvate kinase M2. Biochem. Pharmacol.
79, 1118–1124 (2010).