Metabolic changes associated with tumor metastasis, part 2: Mitochondria, lipid and amino acid metabolism

详细信息    查看全文

• 作者：Paolo E. Porporato ; Valéry L. Payen ; Bjorn Baselet…
• 关键词：Tumor metastasis ; Oxidative phosphorylation (OXPHOS) ; Electron transport chain (ETC) ; Reactive oxygen species (ROS) ; Tricarboxylic acid cycle (TCA cycle) ; Lipogenesis ; Glutaminolysis ; Proline metabolism
• 刊名：Cellular and Molecular Life Sciences (CMLS)
• 出版年：2016
• 出版时间：April 2016
• 年：2016
• 卷：73
• 期：7
• 页码：1349-1363
• 全文大小：772 KB
• 参考文献：1.Gupta GP, Massague J (2006) Cancer metastasis: building a framework. Cell 127:679–695PubMed CrossRef
  2.Warburg O, Wind F, Negelein E (1927) The metabolism of tumors in the body. J Gen Physiol 8:519–530PubMed PubMedCentral CrossRef
  3.Warburg O (1956) On the origin of cancer cell. Science 123:309–314PubMed CrossRef
  4.Carew JS, Huang P (2002) Mitochondrial defects in cancer. Mol Cancer 1:9PubMed PubMedCentral CrossRef
  5.Xiao M, Yang H, Xu W, Ma S, Lin H, Zhu H, Liu L, Liu Y, Yang C, Xu Y, Zhao S, Ye D, Xiong Y, Guan KL (2012) Inhibition of alpha-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Genes Dev 26:1326–1338PubMed PubMedCentral CrossRef
  6.Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, Fantin VR, Jang HG, Jin S, Keenan MC, Marks KM, Prins RM, Ward PS, Yen KE, Liau LM, Rabinowitz JD, Cantley LC, Thompson CB, Vander Heiden MG, Su SM (2009) Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462:739–744PubMed PubMedCentral CrossRef
  7.Kaelin WG Jr (2009) SDH5 mutations and familial paraganglioma: somewhere Warburg is smiling. Cancer Cell 16:180–182PubMed CrossRef
  8.Baysal BE, Ferrell RE, Willett-Brozick JE, Lawrence EC, Myssiorek D, Bosch A, van der Mey A, Taschner PE, Rubinstein WS, Myers EN, Richard CW III, Cornelisse CJ, Devilee P, Devlin B (2000) Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 287:848–851PubMed CrossRef
  9.DeBerardinis RJ, Cheng T (2010) Q’s next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene 29:313–324PubMed PubMedCentral CrossRef
  10.Payen VL, Brisson L, Dewhirst MW, Sonveaux P (2015) Common responses of tumors and wounds to hypoxia. Cancer J 21:75–87PubMed CrossRef
  11.Gough DJ, Corlett A, Schlessinger K, Wegrzyn J, Larner AC, Levy DE (2009) Mitochondrial STAT3 supports Ras-dependent oncogenic transformation. Science 324:1713–1716PubMed PubMedCentral CrossRef
  12.Kang R, Loux T, Tang D, Schapiro NE, Vernon P, Livesey KM, Krasinskas A, Lotze MT, Zeh HJ III (2012) The expression of the receptor for advanced glycation endproducts (RAGE) is permissive for early pancreatic neoplasia. Proc Natl Acad Sci U S A 109:7031–7036PubMed PubMedCentral CrossRef
  13.Rasola A, Sciacovelli M, Chiara F, Pantic B, Brusilow WS, Bernardi P (2010) Activation of mitochondrial ERK protects cancer cells from death through inhibition of the permeability transition. Proc Natl Acad Sci U S A 107:726–731PubMed PubMedCentral CrossRef
  14.Ogura M, Yamaki J, Homma MK, Homma Y (2012) Mitochondrial c-Src regulates cell survival through phosphorylation of respiratory chain components. Biochem J 447:281–289PubMed PubMedCentral CrossRef
  15.Muller FL, Liu Y, Van RH (2004) Complex III releases superoxide to both sides of the inner mitochondrial membrane. J Biol Chem 279:49064–49073PubMed CrossRef
  16.Wellen KE, Thompson CB (2010) Cellular metabolic stress: considering how cells respond to nutrient excess. Mol Cell 40:323–332PubMed PubMedCentral CrossRef
  17.Hsu JL, Hsieh Y, Tu C, O’Connor D, Nick HS, Silverman DN (1996) Catalytic properties of human manganese superoxide dismutase. J Biol Chem 271:17687–17691PubMed CrossRef
  18.Ott M, Robertson JD, Gogvadze V, Zhivotovsky B, Orrenius S (2002) Cytochrome c release from mitochondria proceeds by a two-step process. Proc Natl Acad Sci U S A 99:1259–1263PubMed PubMedCentral CrossRef
  19.Zamzami N, Marchetti P, Castedo M, Decaudin D, Macho A, Hirsch T, Susin SA, Petit PX, Mignotte B, Kroemer G (1995) Sequential reduction of mitochondrial transmembrane potential and generation of reactive oxygen species in early programmed cell death. J Exp Med 182:367–377PubMed CrossRef
  20.Sena LA, Chandel NS (2012) Physiological roles of mitochondrial reactive oxygen species. Mol Cell 48:158–167PubMed PubMedCentral CrossRef
  21.Brunelle JK, Bell EL, Quesada NM, Vercauteren K, Tiranti V, Zeviani M, Scarpulla RC, Chandel NS (2005) Oxygen sensing requires mitochondrial ROS but not oxidative phosphorylation. Cell Metab 1:409–414PubMed CrossRef
  22.Dewaele M, Maes H, Agostinis P (2010) ROS-mediated mechanisms of autophagy stimulation and their relevance in cancer therapy. Autophagy 6:838–854PubMed CrossRef
  23.St-Pierre J, Drori S, Uldry M, Silvaggi JM, Rhee J, Jager S, Handschin C, Zheng K, Lin J, Yang W, Simon DK, Bachoo R, Spiegelman BM (2006) Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell 127:397–408PubMed CrossRef
  24.Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324:1029–1033PubMed PubMedCentral CrossRef
  25.DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB (2008) The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab 7:11–20PubMed CrossRef
  26.Weinberg F, Hamanaka R, Wheaton WW, Weinberg S, Joseph J, Lopez M, Kalyanaraman B, Mutlu GM, Budinger GR, Chandel NS (2010) Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proc Natl Acad Sci U S A 107:8788–8793PubMed PubMedCentral CrossRef
  27.Tan AS, Baty JW, Dong LF, Bezawork-Geleta A, Endaya B, Goodwin J, Bajzikova M, Kovarova J, Peterka M, Yan B, Pesdar EA, Sobol M, Filimonenko A, Stuart S, Vondrusova M, Kluckova K, Sachaphibulkij K, Rohlena J, Hozak P, Truksa J, Eccles D, Haupt LM, Griffiths LR, Neuzil J, Berridge MV (2015) Mitochondrial Genome Acquisition Restores Respiratory Function and Tumorigenic Potential of Cancer Cells without Mitochondrial DNA. Cell Metab 21:81–94PubMed CrossRef
  28.Fogal V, Richardson AD, Karmali PP, Scheffler IE, Smith JW, Ruoslahti E (2010) Mitochondrial p32 protein is a critical regulator of tumor metabolism via maintenance of oxidative phosphorylation. Mol Cell Biol 30:1303–1318PubMed PubMedCentral CrossRef
  29.Viale A, Pettazzoni P, Lyssiotis CA, Ying H, Sanchez N, Marchesini M, Carugo A, Green T, Seth S, Giuliani V, Kost-Alimova M, Muller F, Colla S, Nezi L, Genovese G, Deem AK, Kapoor A, Yao W, Brunetto E, Kang Y, Yuan M, Asara JM, Wang YA, Heffernan TP, Kimmelman AC, Wang H, Fleming JB, Cantley LC, DePinho RA, Draetta GF (2014) Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function. Nature 514:628–632PubMed PubMedCentral CrossRef
  30.Wheaton WW, Weinberg SE, Hamanaka RB, Soberanes S, Sullivan LB, Anso E, Glasauer A, Dufour E, Mutlu GM, Budigner GS, Chandel NS (2014) Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. Elife 3:e02242PubMed PubMedCentral CrossRef
  31.Hirsch HA, Iliopoulos D, Tsichlis PN, Struhl K (2009) Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res 69:7507–7511PubMed PubMedCentral CrossRef
  32.Janzer A, German NJ, Gonzalez-Herrera KN, Asara JM, Haigis MC, Struhl K (2014) Metformin and phenformin deplete tricarboxylic acid cycle and glycolytic intermediates during cell transformation and NTPs in cancer stem cells. Proc Natl Acad Sci U S A 111:10574–10579PubMed PubMedCentral CrossRef
  33.Porporato PE, Payen VL, Perez-Escuredo J, De Saedeleer CJ, Danhier P, Copetti T, Dhup S, Tardy M, Vazeille T, Bouzin C, Feron O, Michiels C, Gallez B, Sonveaux P (2014) A Mitochondrial Switch Promotes Tumor Metastasis. Cell Rep 8:754–766PubMed CrossRef
  34.Comito G, Calvani M, Giannoni E, Bianchini F, Calorini L, Torre E, Migliore C, Giordano S, Chiarugi P (2011) HIF-1alpha stabilization by mitochondrial ROS promotes Met-dependent invasive growth and vasculogenic mimicry in melanoma cells. Free Radic Biol Med 51:893–904PubMed CrossRef
  35.LeBleu VS, O’Connell JT, Gonzalez Herrera KN, Wikman H, Pantel K, Haigis MC, de Carvalho FM, Damascena A, Domingos Chinen LT, Rocha RM, Asara JM, Kalluri R (2014) PGC-1alpha mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis. Nat Cell Biol 16:992–1003PubMed PubMedCentral CrossRef
  36.Chen EI, Hewel J, Krueger JS, Tiraby C, Weber MR, Kralli A, Becker K, Yates JR III, Felding-Habermann B (2007) Adaptation of energy metabolism in breast cancer brain metastases. Cancer Res 67:1472–1486PubMed CrossRef
  37.Caneba CA, Bellance N, Yang L, Pabst L, Nagrath D (2012) Pyruvate uptake is increased in highly invasive ovarian cancer cells under anoikis conditions for anaplerosis, mitochondrial function, and migration. Am J Physiol Endocrinol Metab 303:E1036–E1052PubMed CrossRef
  38.Chen ZX, Pervaiz S (2007) Bcl-2 induces pro-oxidant state by engaging mitochondrial respiration in tumor cells. Cell Death Differ 14:1617–1627PubMed CrossRef
  39.Caino MC, Chae YC, Vaira V, Ferrero S, Nosotti M, Martin NM, Weeraratna A, O’Connell M, Jernigan D, Fatatis A, Languino LR, Bosari S, Altieri DC (2013) Metabolic stress regulates cytoskeletal dynamics and metastasis of cancer cells. J Clin Invest 123:2907–2920PubMed PubMedCentral CrossRef
  40.Lee GH, Yan C, Shin SJ, Hong SC, Ahn T, Moon A, Park SJ, Lee YC, Yoo WH, Kim HT, Kim DS, Chae SW, Kim HR, Chae HJ (2010) BAX inhibitor-1 enhances cancer metastasis by altering glucose metabolism and activating the sodium-hydrogen exchanger: the alteration of mitochondrial function. Oncogene 29:2130–2141PubMed CrossRef
  41.Park J, Kusminski CM, Chua SC, Scherer PE (2010) Leptin receptor signaling supports cancer cell metabolism through suppression of mitochondrial respiration in vivo. Am J Pathol 177:3133–3144PubMed PubMedCentral CrossRef
  42.Liu W, Beck BH, Vaidya KS, Nash KT, Feeley KP, Ballinger SW, Pounds KM, Denning WL, Diers AR, Landar A, Dhar A, Iwakuma T, Welch DR (2014) Metastasis suppressor KISS1 seems to reverse the Warburg effect by enhancing mitochondrial biogenesis. Cancer Res 74:954–963PubMed PubMedCentral CrossRef
  43.Govindarajan B, Sligh JE, Vincent BJ, Li M, Canter JA, Nickoloff BJ, Rodenburg RJ, Smeitink JA, Oberley L, Zhang Y, Slingerland J, Arnold RS, Lambeth JD, Cohen C, Hilenski L, Griendling K, Martinez-Diez M, Cuezva JM, Arbiser JL (2007) Overexpression of Akt converts radial growth melanoma to vertical growth melanoma. J Clin Invest 117:719–729PubMed PubMedCentral CrossRef
  44.Arnold RS, Sun CQ, Richards JC, Grigoriev G, Coleman IM, Nelson PS, Hsieh CL, Lee JK, Xu Z, Rogatko A, Osunkoya AO, Zayzafoon M, Chung L, Petros JA (2009) Mitochondrial DNA mutation stimulates prostate cancer growth in bone stromal environment. Prostate 69:1–11PubMed PubMedCentral CrossRef
  45.Kuo SJ, Chen M, Ma GC, Chen ST, Chang SP, Lin WY, Chen YC, Lee TH, Lin TT, Liu CS (2010) Number of somatic mutations in the mitochondrial D-loop region indicates poor prognosis in breast cancer, independent of TP53 mutation. Cancer Genet Cytogenet 201:94–101PubMed CrossRef
  46.Ebner S, Lang R, Mueller EE, Eder W, Oeller M, Moser A, Koller J, Paulweber B, Mayr JA, Sperl W, Kofler B (2011) Mitochondrial haplogroups, control region polymorphisms and malignant melanoma: a study in middle European Caucasians. PLoS ONE 6:e27192PubMed PubMedCentral CrossRef
  47.Amuthan G, Biswas G, Ananadatheerthavarada HK, Vijayasarathy C, Shephard HM, Avadhani NG (2002) Mitochondrial stress-induced calcium signaling, phenotypic changes and invasive behavior in human lung carcinoma A549 cells. Oncogene 21:7839–7849PubMed CrossRef
  48.Amuthan G, Biswas G, Zhang SY, Klein-Szanto A, Vijayasarathy C, Avadhani NG (2001) Mitochondria-to-nucleus stress signaling induces phenotypic changes, tumor progression and cell invasion. EMBO J 20:1910–1920PubMed PubMedCentral CrossRef
  49.Samudio I, Harmancey R, Fiegl M, Kantarjian H, Konopleva M, Korchin B, Kaluarachchi K, Bornmann W, Duvvuri S, Taegtmeyer H, Andreeff M (2010) Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction. J Clin Invest 120:142–156PubMed PubMedCentral CrossRef
  50.Girnun GD (2012) The diverse role of the PPARgamma coactivator 1 family of transcriptional coactivators in cancer. Semin Cell Dev Biol 23:381–388PubMed PubMedCentral CrossRef
  51.Ghosh JC, Siegelin MD, Vaira V, Faversani A, Tavecchio M, Chae YC, Lisanti S, Rampini P, Giroda M, Caino MC, Seo JH, Kossenkov AV, Michalek RD, Schultz DC, Bosari S, Languino LR, Altieri DC (2015) Adaptive mitochondrial reprogramming and resistance to PI3K therapy. J Natl Cancer Inst. doi:10.​1093/​jnci/​dju502
  52.Smallbone K, Gatenby RA, Gillies RJ, Maini PK, Gavaghan DJ (2007) Metabolic changes during carcinogenesis: potential impact on invasiveness. J Theor Biol 244:703–713PubMed CrossRef
  53.Santidrian AF, Matsuno-Yagi A, Ritland M, Seo BB, LeBoeuf SE, Gay LJ, Yagi T, Felding-Habermann B (2013) Mitochondrial complex I activity and NAD +/NADH balance regulate breast cancer progression. J Clin Invest 123:1068–1081PubMed PubMedCentral CrossRef
  54.Singh RK, Srivastava A, Kalaiarasan P, Manvati S, Chopra R, Bamezai RN (2014) mtDNA germ line variation mediated ROS generates retrograde signaling and induces pro-cancerous metabolic features. Sci Rep 4:6571PubMed PubMedCentral CrossRef
  55.Chiarugi P (2005) PTPs versus PTKs: the redox side of the coin. Free Radic Res 39:353–364PubMed CrossRef
  56.Zarse K, Schmeisser S, Groth M, Priebe S, Beuster G, Kuhlow D, Guthke R, Platzer M, Kahn CR, Ristow M (2012) Impaired insulin/IGF1 signaling extends life span by promoting mitochondrial l -proline catabolism to induce a transient ROS signal. Cell Metab 15:451–465PubMed CrossRef
  57.Ristow M (2014) Unraveling the truth about antioxidants: mitohormesis explains ROS-induced health benefits. Nat Med 20:709–711PubMed CrossRef
  58.Porporato PE, Sonveaux P (2015) Paving the way for a therapeutic prevention of tumor metastasis with agents targeting mitochondrial superoxide. Mol Cell Oncol. doi:10.​4161/​23723548.​2014.​968043
  59.Szatrowski TP, Nathan CF (1991) Production of large amounts of hydrogen peroxide by human tumor cells. Cancer Res 51:794–798PubMed
  60.Ishikawa K, Takenaga K, Akimoto M, Koshikawa N, Yamaguchi A, Imanishi H, Nakada K, Honma Y, Hayashi J (2008) ROS-generating mitochondrial DNA mutations can regulate tumor cell metastasis. Science 320:661–664PubMed CrossRef
  61.Chang J, Jung HJ, Jeong SH, Kim HK, Han J, Kwon HJ (2014) A mutation in the mitochondrial protein UQCRB promotes angiogenesis through the generation of mitochondrial reactive oxygen species. Biochem Biophys Res Commun 455:290–297PubMed CrossRef
  62.Kaipparettu BA, Ma Y, Park JH, Lee TL, Zhang Y, Yotnda P, Creighton CJ, Chan WY, Wong LJ (2013) Crosstalk from non-cancerous mitochondria can inhibit tumor properties of metastatic cells by suppressing oncogenic pathways. PLoS One 8:e61747PubMed PubMedCentral CrossRef
  63.Dasgupta S, Hoque MO, Upadhyay S, Sidransky D (2008) Mitochondrial cytochrome B gene mutation promotes tumor growth in bladder cancer. Cancer Res 68:700–706PubMed CrossRef
  64.Ali MH, Mungai PT, Schumacker PT (2006) Stretch-induced phosphorylation of focal adhesion kinase in endothelial cells: role of mitochondrial oxidants. Am J Physiol Lung Cell Mol Physiol 291:L38–L45PubMed CrossRef
  65.Radisky DC, Levy DD, Littlepage LE, Liu H, Nelson CM, Fata JE, Leake D, Godden EL, Albertson DG, Nieto MA, Werb Z, Bissell MJ (2005) Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature 436:123–127PubMed PubMedCentral CrossRef
  66.Imhoff BR, Hansen JM (2009) Extracellular redox status regulates Nrf2 activation through mitochondrial reactive oxygen species. Biochem J 424:491–500PubMed CrossRef
  67.Lluis JM, Buricchi F, Chiarugi P, Morales A, Fernandez-Checa JC (2007) Dual role of mitochondrial reactive oxygen species in hypoxia signaling: activation of nuclear factor-{kappa}B via c-SRC and oxidant-dependent cell death. Cancer Res 67:7368–7377PubMed CrossRef
  68.DeNicola GM, Karreth FA, Humpton TJ, Gopinathan A, Wei C, Frese K, Mangal D, Yu KH, Yeo CJ, Calhoun ES, Scrimieri F, Winter JM, Hruban RH, Iacobuzio-Donahue C, Kern SE, Blair IA, Tuveson DA (2011) Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature 475:106–109PubMed PubMedCentral CrossRef
  69.Assefa Z, Vantieghem A, Declercq W, Vandenabeele P, Vandenheede JR, Merlevede W, de WP WP, Agostinis P (1999) The activation of the c-Jun N-terminal kinase and p38 mitogen-activated protein kinase signaling pathways protects HeLa cells from apoptosis following photodynamic therapy with hypericin. J Biol Chem 274:8788–8796PubMed CrossRef
  70.Chandel NS, Tuveson DA (2014) The promise and perils of antioxidants for cancer patients. N Engl J Med 371:177–178PubMed CrossRef
  71.Ishikawa K, Hashizume O, Koshikawa N, Fukuda S, Nakada K, Takenaga K, Hayashi J (2008) Enhanced glycolysis induced by mtDNA mutations does not regulate metastasis. FEBS Lett 582:3525–3530PubMed CrossRef
  72.Gasparre G, Romeo G, Rugolo M, Porcelli AM (2011) Learning from oncocytic tumors: why choose inefficient mitochondria? Biochim Biophys Acta 1807:633–642PubMed CrossRef
  73.Tallini G (1998) Oncocytic tumours. Virchows Arch 433:5–12PubMed CrossRef
  74.Gasparre G, Hervouet E, De LE, Demont J, Pennisi LF, Colombel M, Mege-Lechevallier F, Scoazec JY, Bonora E, Smeets R, Smeitink J, Lazar V, Lespinasse J, Giraud S, Godinot C, Romeo G, Simonnet H (2008) Clonal expansion of mutated mitochondrial DNA is associated with tumor formation and complex I deficiency in the benign renal oncocytoma. Hum Mol Genet 17:986–995PubMed CrossRef
  75.Mayr JA, Meierhofer D, Zimmermann F, Feichtinger R, Kogler C, Ratschek M, Schmeller N, Sperl W, Kofler B (2008) Loss of complex I due to mitochondrial DNA mutations in renal oncocytoma. Clin Cancer Res 14:2270–2275PubMed CrossRef
  76.Schlichtholz B, Turyn J, Goyke E, Biernacki M, Jaskiewicz K, Sledzinski Z, Swierczynski J (2005) Enhanced citrate synthase activity in human pancreatic cancer. Pancreas 30:99–104PubMed CrossRef
  77.Chen L, Liu T, Zhou J, Wang Y, Wang X, Di W, Zhang S (2014) Citrate synthase expression affects tumor phenotype and drug resistance in human ovarian carcinoma. PLoS ONE 9:e115708PubMed PubMedCentral CrossRef
  78.Lin CC, Cheng TL, Tsai WH, Tsai HJ, Hu KH, Chang HC, Yeh CW, Chen YC, Liao CC, Chang WT (2012) Loss of the respiratory enzyme citrate synthase directly links the Warburg effect to tumor malignancy. Sci Rep 2:785
  79.Singh KK, Desouki MM, Franklin RB, Costello LC (2006) Mitochondrial aconitase and citrate metabolism in malignant and nonmalignant human prostate tissues. Mol Cancer 5:14PubMed PubMedCentral CrossRef
  80.Mycielska ME, Broke-Smith TP, Palmer CP, Beckerman R, Nastos T, Erguler K, Djamgoz MB (2006) Citrate enhances in vitro metastatic behaviours of PC-3M human prostate cancer cells: status of endogenous citrate and dependence on aconitase and fatty acid synthase. Int J Biochem Cell Biol 38:1766–1777PubMed CrossRef
  81.Loenarz C, Schofield CJ (2008) Expanding chemical biology of 2-oxoglutarate oxygenases. Nat Chem Biol 4:152–156PubMed CrossRef
  82.Carey BW, Finley LW, Cross JR, Allis CD, Thompson CB (2015) Intracellular alpha-ketoglutarate maintains the pluripotency of embryonic stem cells. Nature 518:413–416PubMed PubMedCentral CrossRef
  83.Berra E, Richard DE, Gothie E, Pouyssegur J (2001) HIF-1-dependent transcriptional activity is required for oxygen-mediated HIF-1alpha degradation. FEBS Lett 491:85–90PubMed CrossRef
  84.Duran RV, Oppliger W, Robitaille AM, Heiserich L, Skendaj R, Gottlieb E, Hall MN (2012) Glutaminolysis activates Rag-mTORC1 signaling. Mol Cell 47:349–358PubMed CrossRef
  85.Chin RM, Fu X, Pai MY, Vergnes L, Hwang H, Deng G, Diep S, Lomenick B, Meli VS, Monsalve GC, Hu E, Whelan SA, Wang JX, Jung G, Solis GM, Fazlollahi F, Kaweeteerawat C, Quach A, Nili M, Krall AS, Godwin HA, Chang HR, Faull KF, Guo F, Jiang M, Trauger SA, Saghatelian A, Braas D, Christofk HR, Clarke CF, Teitell MA, Petrascheck M, Reue K, Jung ME, Frand AR, Huang J (2014) The metabolite alpha-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR. Nature 510:397–401PubMed PubMedCentral
  86.Wang JB, Erickson JW, Fuji R, Ramachandran S, Gao P, Dinavahi R, Wilson KF, Ambrosio AL, Dias SM, Dang CV, Cerione RA (2010) Targeting mitochondrial glutaminase activity inhibits oncogenic transformation. Cancer Cell 18:207–219PubMed PubMedCentral CrossRef
  87.Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, Friedman H, Friedman A, Reardon D, Herndon J, Kinzler KW, Velculescu VE, Vogelstein B, Bigner DD (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:765–773PubMed PubMedCentral CrossRef
  88.Ward PS, Cross JR, Lu C, Weigert O, Abel-Wahab O, Levine RL, Weinstock DM, Sharp KA, Thompson CB (2012) Identification of additional IDH mutations associated with oncometabolite R(-)-2-hydroxyglutarate production. Oncogene 31:2491–2498PubMed PubMedCentral CrossRef
  89.Mardis ER, Ding L, Dooling DJ, Larson DE, McLellan MD, Chen K, Koboldt DC, Fulton RS, Delehaunty KD, McGrath SD, Fulton LA, Locke DP, Magrini VJ, Abbott RM, Vickery TL, Reed JS, Robinson JS, Wylie T, Smith SM, Carmichael L, Eldred JM, Harris CC, Walker J, Peck JB, Du F, Dukes AF, Sanderson GE, Brummett AM, Clark E, McMichael JF, Meyer RJ, Schindler JK, Pohl CS, Wallis JW, Shi X, Lin L, Schmidt H, Tang Y, Haipek C, Wiechert ME, Ivy JV, Kalicki J, Elliott G, Ries RE, Payton JE, Westervelt P, Tomasson MH, Watson MA, Baty J, Heath S, Shannon WD, Nagarajan R, Link DC, Walter MJ, Graubert TA, DiPersio JF, Wilson RK, Ley TJ (2009) Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med 361:1058–1066PubMed PubMedCentral CrossRef
  90.Hirata M, Sasaki M, Cairns RA, Inoue S, Puviindran V, Li WY, Snow BE, Jones LD, Wei Q, Sato S, Tang YJ, Nadesan P, Rockel J, Whetstone H, Poon R, Weng A, Gross S, Straley K, Gliser C, Xu Y, Wunder J, Mak TW, Alman BA (2015) Mutant IDH is sufficient to initiate enchondromatosis in mice. Proc Natl Acad Sci USA 112:2829–2834PubMed PubMedCentral CrossRef
  91.Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH, Ito S, Yang C, Wang P, Xiao MT, Liu LX, Jiang WQ, Liu J, Zhang JY, Wang B, Frye S, Zhang Y, Xu YH, Lei QY, Guan KL, Zhao SM, Xiong Y (2011) Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell 19:17–30PubMed PubMedCentral CrossRef
  92.Fu Y, Zheng Y, Li K, Huang R, Zheng S, An N, Liang A (2012) Mutations in isocitrate dehydrogenase 2 accelerate glioma cell migration via matrix metalloproteinase-2 and 9. Biotechnol Lett 34:441–446PubMed CrossRef
  93.Astuti D, Douglas F, Lennard TW, Aligianis IA, Woodward ER, Evans DG, Eng C, Latif F, Maher ER (2001) Germline SDHD mutation in familial phaeochromocytoma. Lancet 357:1181–1182PubMed CrossRef
  94.Neumann HP, Bausch B, McWhinney SR, Bender BU, Gimm O, Franke G, Schipper J, Klisch J, Altehoefer C, Zerres K, Januszewicz A, Eng C, Smith WM, Munk R, Manz T, Glaesker S, Apel TW, Treier M, Reineke M, Walz MK, Hoang-Vu C, Brauckhoff M, Klein-Franke A, Klose P, Schmidt H, Maier-Woelfle M, Peczkowska M, Szmigielski C, Eng C (2002) Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med 346:1459–1466PubMed CrossRef
  95.Ricketts C, Woodward ER, Killick P, Morris MR, Astuti D, Latif F, Maher ER (2008) Germline SDHB mutations and familial renal cell carcinoma. J Natl Cancer Inst 100:1260–1262PubMed CrossRef
  96.Janeway KA, Kim SY, Lodish M, Nose V, Rustin P, Gaal J, Dahia PL, Liegl B, Ball ER, Raygada M, Lai AH, Kelly L, Hornick JL, O’Sullivan M, de Krijger RR, Dinjens WN, Demetri GD, Antonescu CR, Fletcher JA, Helman L, Stratakis CA (2011) Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. Proc Natl Acad Sci U S A 108:314–318PubMed PubMedCentral CrossRef
  97.Selak MA, Armour SM, MacKenzie ED, Boulahbel H, Watson DG, Mansfield KD, Pan Y, Simon MC, Thompson CB, Gottlieb E (2005) Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell 7:77–85PubMed CrossRef
  98.Kiuru M, Lehtonen R, Arola J, Salovaara R, Jarvinen H, Aittomaki K, Sjoberg J, Visakorpi T, Knuutila S, Isola J, Delahunt B, Herva R, Launonen V, Karhu A, Aaltonen LA (2002) Few FH mutations in sporadic counterparts of tumor types observed in hereditary leiomyomatosis and renal cell cancer families. Cancer Res 62:4554–4557PubMed
  99.Tomlinson IP, Alam NA, Rowan AJ, Barclay E, Jaeger EE, Kelsell D, Leigh I, Gorman P, Lamlum H, Rahman S, Roylance RR, Olpin S, Bevan S, Barker K, Hearle N, Houlston RS, Kiuru M, Lehtonen R, Karhu A, Vilkki S, Laiho P, Eklund C, Vierimaa O, Aittomaki K, Hietala M, Sistonen P, Paetau A, Salovaara R, Herva R, Launonen V, Aaltonen LA (2002) Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet 30:406–410PubMed CrossRef
  100.Castro-Vega LJ, Buffet A, De Cubas AA, Cascon A, Menara M, Khalifa E, Amar L, Azriel S, Bourdeau I, Chabre O, Curras-Freixes M, Franco-Vidal V, Guillaud-Bataille M, Simian C, Morin A, Leton R, Gomez-Grana A, Pollard PJ, Rustin P, Robledo M, Favier J, Gimenez-Roqueplo AP (2014) Germline mutations in FH confer predisposition to malignant pheochromocytomas and paragangliomas. Hum Mol Genet 23:2440–2446PubMed CrossRef
  101.Kaelin WG Jr (2011) Cancer and altered metabolism: potential importance of hypoxia-inducible factor and 2-oxoglutarate-dependent dioxygenases. Cold Spring Harb Symp Quant Biol 76:335–345PubMed PubMedCentral CrossRef
  102.Letouze E, Martinelli C, Loriot C, Burnichon N, Abermil N, Ottolenghi C, Janin M, Menara M, Nguyen AT, Benit P, Buffet A, Marcaillou C, Bertherat J, Amar L, Rustin P, De RA, Gimenez-Roqueplo AP, Favier J (2013) SDH mutations establish a hypermethylator phenotype in paraganglioma. Cancer Cell 23:739–752PubMed CrossRef
  103.King A, Selak MA, Gottlieb E (2006) Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer. Oncogene 25:4675–4682PubMed CrossRef
  104.Nagai R, Brock JW, Blatnik M, Baatz JE, Bethard J, Walla MD, Thorpe SR, Baynes JW, Frizzell N (2007) Succination of protein thiols during adipocyte maturation: a biomarker of mitochondrial stress. J Biol Chem 282:34219–34228PubMed CrossRef
  105.Adam J, Hatipoglu E, O’Flaherty L, Ternette N, Sahgal N, Lockstone H, Baban D, Nye E, Stamp GW, Wolhuter K, Stevens M, Fischer R, Carmeliet P, Maxwell PH, Pugh CW, Frizzell N, Soga T, Kessler BM, El-Bahrawy M, Ratcliffe PJ, Pollard PJ (2011) 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 20:524–537PubMed PubMedCentral CrossRef
  106.Ooi A, Wong JC, Petillo D, Roossien D, Perrier-Trudova V, Whitten D, Min BW, Tan MH, Zhang Z, Yang XJ, Zhou M, Gardie B, Molinie V, Richard S, Tan PH, Teh BT, Furge KA (2011) An antioxidant response phenotype shared between hereditary and sporadic type 2 papillary renal cell carcinoma. Cancer Cell 20:511–523PubMed CrossRef
  107.Zheng L, Cardaci S, Jerby L, MacKenzie ED, Sciacovelli M, Johnson TI, Gaude E, King A, Leach JD, Edrada-Ebel R, Hedley A, Morrice NA, Kalna G, Blyth K, Ruppin E, Frezza C, Gottlieb E (2015) Fumarate induces redox-dependent senescence by modifying glutathione metabolism. Nat Commun 6:6001PubMed PubMedCentral CrossRef
  108.Sudarshan S, Shanmugasundaram K, Naylor SL, Lin S, Livi CB, O’Neill CF, Parekh DJ, Yeh IT, Sun LZ, Block K (2011) Reduced expression of fumarate hydratase in clear cell renal cancer mediates HIF-2alpha accumulation and promotes migration and invasion. PLoS One 6:e21037PubMed PubMedCentral CrossRef
  109.Loewe R, Valero T, Kremling S, Pratscher B, Kunstfeld R, Pehamberger H, Petzelbauer P (2006) Dimethylfumarate impairs melanoma growth and metastasis. Cancer Res 66:11888–11896PubMed CrossRef
  110.Yamazoe Y, Tsubaki M, Matsuoka H, Satou T, Itoh T, Kusunoki T, Kidera Y, Tanimori Y, Shoji K, Nakamura H, Ogaki M, Nishiura S, Nishida S (2009) Dimethylfumarate inhibits tumor cell invasion and metastasis by suppressing the expression and activities of matrix metalloproteinases in melanoma cells. Cell Biol Int 33:1087–1094PubMed CrossRef
  111.Valero T, Steele S, Neumuller K, Bracher A, Niederleithner H, Pehamberger H, Petzelbauer P, Loewe R (2010) Combination of dacarbazine and dimethylfumarate efficiently reduces melanoma lymph node metastasis. J Invest Dermatol 130:1087–1094PubMed CrossRef
  112.Liu J, Gao L, Zhang H, Wang D, Wang M, Zhu J, Pang C, Wang C (2013) Succinate dehydrogenase 5 (SDH5) regulates glycogen synthase kinase 3beta-beta-catenin-mediated lung cancer metastasis. J Biol Chem 288:29965–29973PubMed PubMedCentral CrossRef
  113.Holleran AL, Briscoe DA, Fiskum G, Kelleher JK (1995) Glutamine metabolism in AS-30D hepatoma cells. Evidence for its conversion into lipids via reductive carboxylation. Mol Cell Biochem 152:95–101PubMed CrossRef
  114.Metallo CM, Gameiro PA, Bell EL, Mattaini KR, Yang J, Hiller K, Jewell CM, Johnson ZR, Irvine DJ, Guarente L, Kelleher JK, Vander Heiden MG, Iliopoulos O, Stephanopoulos G (2012) Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 481:380–384
  115.Mullen AR, Wheaton WW, Jin ES, Chen PH, Sullivan LB, Cheng T, Yang Y, Linehan WM, Chandel NS, DeBerardinis RJ (2012) Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature 481:385–388PubMedCentral
  116.Fendt SM, Bell EL, Keibler MA, Olenchock BA, Mayers JR, Wasylenko TM, Vokes NI, Guarente L, Vander Heiden MG, Stephanopoulos G (2013) Reductive glutamine metabolism is a function of the alpha-ketoglutarate to citrate ratio in cells. Nat Commun 4:2236PubMed PubMedCentral CrossRef
  117.Filipp FV, Scott DA, Ronai ZA, Osterman AL, Smith JW (2012) Reverse TCA cycle flux through isocitrate dehydrogenases 1 and 2 is required for lipogenesis in hypoxic melanoma cells. Pigment Cell Melanoma Res 25:375–383PubMed PubMedCentral CrossRef
  118.Mullen AR, Hu Z, Shi X, Jiang L, Boroughs LK, Kovacs Z, Boriack R, Rakheja D, Sullivan LB, Linehan WM, Chandel NS, DeBerardinis RJ (2014) Oxidation of alpha-ketoglutarate is required for reductive carboxylation in cancer cells with mitochondrial defects. Cell Rep 7:1679–1690PubMed PubMedCentral CrossRef
  119.Sun RC, Denko NC (2014) Hypoxic regulation of glutamine metabolism through HIF1 and SIAH2 supports lipid synthesis that is necessary for tumor growth. Cell Metab 19:285–292PubMed PubMedCentral CrossRef
  120.Dasgupta S, Putluri N, Long W, Zhang B, Wang J, Kaushik AK, Arnold JM, Bhowmik SK, Stashi E, Brennan CA, Rajapakshe K, Coarfa C, Mitsiades N, Ittmann MM, Chinnaiyan AM, Sreekumar A, O’Malley BW (2015) Coactivator SRC-2-dependent metabolic reprogramming mediates prostate cancer survival and metastasis. J Clin Invest 125:1174–1188PubMed PubMedCentral CrossRef
  121.Qin J, Lee HJ, Wu SP, Lin SC, Lanz RB, Creighton CJ, DeMayo FJ, Tsai SY, Tsai MJ (2014) Androgen deprivation-induced NCoA2 promotes metastatic and castration-resistant prostate cancer. J Clin Invest 124:5013–5026PubMed PubMedCentral CrossRef
  122.Hsu PP, Sabatini DM (2008) Cancer cell metabolism: warburg and beyond. Cell 134:703–707PubMed CrossRef
  123.Horton JD, Goldstein JL, Brown MS (2002) SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest 109:1125–1131PubMed PubMedCentral CrossRef
  124.Yamauchi Y, Furukawa K, Hamamura K, Furukawa K (2011) Positive feedback loop between PI3 K-Akt-mTORC1 signaling and the lipogenic pathway boosts Akt signaling: induction of the lipogenic pathway by a melanoma antigen. Cancer Res 71:4989–4997PubMed CrossRef
  125.Griffiths B, Lewis CA, Bensaad K, Ros S, Zhang Q, Ferber EC, Konisti S, Peck B, Miess H, East P, Wakelam M, Harris AL, Schulze A (2013) Sterol regulatory element binding protein-dependent regulation of lipid synthesis supports cell survival and tumor growth. Cancer Metab 1:3PubMed PubMedCentral CrossRef
  126.Lewis CA, Brault C, Peck B, Bensaad K, Griffiths B, Mitter R, Chakravarty P, East P, Dankworth B, Alibhai D, Harris AL, Schulze A (2015) SREBP maintains lipid biosynthesis and viability of cancer cells under lipid- and oxygen-deprived conditions and defines a gene signature associated with poor survival in glioblastoma multiforme. Oncogene. doi:10.​1038/​onc.​2014.​439 PubMedCentral
  127.Pitroda SP, Khodarev NN, Beckett MA, Kufe DW, Weichselbaum RR (2009) MUC1-induced alterations in a lipid metabolic gene network predict response of human breast cancers to tamoxifen treatment. Proc Natl Acad Sci U S A 106:5837–5841PubMed PubMedCentral CrossRef
  128.Zhao Q, Barclay M, Hilkens J, Guo X, Barrow H, Rhodes JM, Yu LG (2010) Interaction between circulating galectin-3 and cancer-associated MUC1 enhances tumour cell homotypic aggregation and prevents anoikis. Mol Cancer 9:154PubMed PubMedCentral CrossRef
  129.Flavin R, Peluso S, Nguyen PL, Loda M (2010) Fatty acid synthase as a potential therapeutic target in cancer. Future Oncol 6:551–562PubMed PubMedCentral CrossRef
  130.Migita T, Ruiz S, Fornari A, Fiorentino M, Priolo C, Zadra G, Inazuka F, Grisanzio C, Palescandolo E, Shin E, Fiore C, Xie W, Kung AL, Febbo PG, Subramanian A, Mucci L, Ma J, Signoretti S, Stampfer M, Hahn WC, Finn S, Loda M (2009) Fatty acid synthase: a metabolic enzyme and candidate oncogene in prostate cancer. J Natl Cancer Inst 101:519–532PubMed PubMedCentral CrossRef
  131.Hatzivassiliou G, Zhao F, Bauer DE, Andreadis C, Shaw AN, Dhanak D, Hingorani SR, Tuveson DA, Thompson CB (2005) ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell 8:311–321PubMed CrossRef
  132.Migita T, Narita T, Nomura K, Miyagi E, Inazuka F, Matsuura M, Ushijima M, Mashima T, Seimiya H, Satoh Y, Okumura S, Nakagawa K, Ishikawa Y (2008) ATP citrate lyase: activation and therapeutic implications in non-small cell lung cancer. Cancer Res 68:8547–8554PubMed CrossRef
  133.Alo’ PL, Visca P, Marci A, Mangoni A, Botti C, Di TU (1996) Expression of fatty acid synthase (FAS) as a predictor of recurrence in stage I breast carcinoma patients. Cancer 77:474–482PubMed CrossRef
  134.Camassei FD, Cozza R, Acquaviva A, Jenkner A, Rava L, Gareri R, Donfrancesco A, Bosman C, Vadala P, Hadjistilianou T, Boldrini R (2003) Expression of the lipogenic enzyme fatty acid synthase (FAS) in retinoblastoma and its correlation with tumor aggressiveness. Invest Ophthalmol Vis Sci 44:2399–2403PubMed CrossRef
  135.Luque-Garcia JL, Martinez-Torrecuadrada JL, Epifano C, Canamero M, Babel I, Casal JI (2010) Differential protein expression on the cell surface of colorectal cancer cells associated to tumor metastasis. Proteomics 10:940–952PubMed
  136.Zaytseva YY, Rychahou PG, Gulhati P, Elliott VA, Mustain WC, O’Connor K, Morris AJ, Sunkara M, Weiss HL, Lee EY, Evers BM (2012) Inhibition of fatty acid synthase attenuates CD44-associated signaling and reduces metastasis in colorectal cancer. Cancer Res 72:1504–1517PubMed PubMedCentral CrossRef
  137.Sounni NE, Cimino J, Blacher S, Primac I, Truong A, Mazzucchelli G, Paye A, Calligaris D, Debois D, De TP, Mari B, De PE, Noel A (2014) Blocking lipid synthesis overcomes tumor regrowth and metastasis after antiangiogenic therapy withdrawal. Cell Metab 20:280–294PubMed CrossRef
  138.Paez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Vinals F, Inoue M, Bergers G, Hanahan D, Casanovas O (2009) Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 15:220–231PubMed PubMedCentral CrossRef
  139.Antalis CJ, Uchida A, Buhman KK, Siddiqui RA (2011) Migration of MDA-MB-231 breast cancer cells depends on the availability of exogenous lipids and cholesterol esterification. Clin Exp Metastasis 28:733–741PubMed CrossRef
  140.Jiang L, Xiao L, Sugiura H, Huang X, Ali A, Kuro O, DeBerardinis RJ, Boothman DA (2015) Metabolic reprogramming during TGFbeta1-induced epithelial-to-mesenchymal transition. Oncogene 34:3908–3916PubMed PubMedCentral CrossRef
  141.Dirat B, Bochet L, Dabek M, Daviaud D, Dauvillier S, Majed B, Wang YY, Meulle A, Salles B, Le GS, Garrido I, Escourrou G, Valet P, Muller C (2011) Cancer-associated adipocytes exhibit an activated phenotype and contribute to breast cancer invasion. Cancer Res 71:2455–2465PubMed CrossRef
  142.Nieman KM, Kenny HA, Penicka CV, Ladanyi A, Buell-Gutbrod R, Zillhardt MR, Romero IL, Carey MS, Mills GB, Hotamisligil GS, Yamada SD, Peter ME, Gwin K, Lengyel E (2011) Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat Med 17:1498–1503PubMed PubMedCentral CrossRef
  143.Medina MA, Marquez J, Nunez DCI (1992) Interchange of amino acids between tumor and host. Biochem Med Metab Biol 48:1–7PubMed CrossRef
  144.Board M, Humm S, Newsholme EA (1990) Maximum activities of key enzymes of glycolysis, glutaminolysis, pentose phosphate pathway and tricarboxylic acid cycle in normal, neoplastic and suppressed cells. Biochem J 265:503–509PubMed PubMedCentral CrossRef
  145.Liu W, Le A, Hancock C, Lane AN, Dang CV, Fan TW, Phang JM (2012) Reprogramming of proline and glutamine metabolism contributes to the proliferative and metabolic responses regulated by oncogenic transcription factor c-MYC. Proc Natl Acad Sci U S A 109:8983–8988PubMed PubMedCentral CrossRef
  146.Son J, Lyssiotis CA, Ying H, Wang X, Hua S, Ligorio M, Perera RM, Ferrone CR, Mullarky E, Shyh-Chang N, Kang Y, Fleming JB, Bardeesy N, Asara JM, Haigis MC, DePinho RA, Cantley LC, Kimmelman AC (2013) Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature 496:101–105PubMed PubMedCentral CrossRef
  147.Ulanet DB, Couto K, Jha A, Choe S, Wang A, Woo HK, Steadman M, DeLaBarre B, Gross S, Driggers E, Dorsch M, Hurov JB (2014) Mesenchymal phenotype predisposes lung cancer cells to impaired proliferation and redox stress in response to glutaminase inhibition. PLoS ONE 9:e115144PubMed PubMedCentral CrossRef
  148.Wang JW, Peng SY, Li JT, Wang Y, Zhang ZP, Cheng Y, Cheng DQ, Weng WH, Wu XS, Fei XZ, Quan ZW, Li JY, Li SG, Liu YB (2009) Identification of metastasis-associated proteins involved in gallbladder carcinoma metastasis by proteomic analysis and functional exploration of chloride intracellular channel 1. Cancer Lett 281:71–81PubMed CrossRef
  149.Liu S, Sun MZ, Tang JW, Wang Z, Sun C, Greenaway FT (2008) High-performance liquid chromatography/nano-electrospray ionization tandem mass spectrometry, two-dimensional difference in-gel electrophoresis and gene microarray identification of lymphatic metastasis-associated biomarkers. Rapid Commun Mass Spectrom 22:3172–3178PubMed CrossRef
  150.Jin L, Li D, Alesi GN, Fan J, Kang HB, Lu Z, Boggon TJ, Jin P, Yi H, Wright ER, Duong D, Seyfried NT, Egnatchik R, DeBerardinis RJ, Magliocca KR, He C, Arellano ML, Khoury HJ, Shin DM, Khuri FR, Kang S (2015) Glutamate dehydrogenase 1 signals through antioxidant glutathione peroxidase 1 to regulate redox homeostasis and tumor growth. Cancer Cell 27:257–270PubMed PubMedCentral CrossRef
  151.Liu Y, Borchert GL, Surazynski A, Hu CA, Phang JM (2006) Proline oxidase activates both intrinsic and extrinsic pathways for apoptosis: the role of ROS/superoxides, NFAT and MEK/ERK signaling. Oncogene 25:5640–5647PubMed CrossRef
  152.Miyagi Y, Higashiyama M, Gochi A, Akaike M, Ishikawa T, Miura T, Saruki N, Bando E, Kimura H, Imamura F, Moriyama M, Ikeda I, Chiba A, Oshita F, Imaizumi A, Yamamoto H, Miyano H, Horimoto K, Tochikubo O, Mitsushima T, Yamakado M, Okamoto N (2011) Plasma free amino acid profiling of five types of cancer patients and its application for early detection. PLoS ONE 6:e24143PubMed PubMedCentral CrossRef
  153.Steven FS, Griffin MM, Itzhaki S, Al-Habib A (1980) A trypsin-like neutral protease on Ehrlich ascites cell surfaces: its role in the activation of tumour-cell zymogen of collagenase. Br J Cancer 42:712–721PubMed PubMedCentral CrossRef
  154.Liu W, Glunde K, Bhujwalla ZM, Raman V, Sharma A, Phang JM (2012) Proline oxidase promotes tumor cell survival in hypoxic tumor microenvironments. Cancer Res 72:3677–3686PubMed PubMedCentral CrossRef
  155.Togashi Y, Arao T, Kato H, Matsumoto K, Terashima M, Hayashi H, de Velasco MA, Fujita Y, Kimura H, Yasuda T, Shiozaki H, Nishio K (2014) Frequent amplification of ORAOV1 gene in esophageal squamous cell cancer promotes an aggressive phenotype via proline metabolism and ROS production. Oncotarget 5:2962–2973PubMed PubMedCentral CrossRef
  156.Comes S, Gagliardi M, Laprano N, Fico A, Cimmino A, Palamidessi A, De CD, De FS, Angelini C, Scita G, Patriarca EJ, Matarazzo MR, Minchiotti G (2013) L-Proline induces a mesenchymal-like invasive program in embryonic stem cells by remodeling H3K9 and H3K36 methylation. Stem Cell Reports 1:307–321PubMed PubMedCentral CrossRef
  157.Uyttenhove C, Pilotte L, Theate I, Stroobant V, Colau D, Parmentier N, Boon T, Van Den Eynde BJ (2003) Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med 9:1269–1274PubMed CrossRef
  158.Tanizaki Y, Kobayashi A, Toujima S, Shiro M, Mizoguchi M, Mabuchi Y, Yagi S, Minami S, Takikawa O, Ino K (2014) Indoleamine 2,3-dioxygenase promotes peritoneal metastasis of ovarian cancer by inducing an immunosuppressive environment. Cancer Sci 105:966–973PubMed PubMedCentral CrossRef
  159.Ryu HS, Park YS, Park HJ, Chung YR, Yom CK, Ahn SH, Park YJ, Park SH, Park SY (2014) Expression of indoleamine 2,3-dioxygenase and infiltration of FOXP3 + regulatory T cells are associated with aggressive features of papillary thyroid microcarcinoma. Thyroid 24:1232–1240PubMed CrossRef
  160.Chen JY, Li CF, Kuo CC, Tsai KK, Hou MF, Hung WC (2014) Cancer/stroma interplay via cyclooxygenase-2 and indoleamine 2,3-dioxygenase promotes breast cancer progression. Breast Cancer Res 16:410PubMed PubMedCentral CrossRef
  161.Speeckaert R, Vermaelen K, van GN, Autier P, Lambert J, Haspeslagh M, van GM, Thielemans K, Neyns B, Roche N, Verbeke N, Deron P, Speeckaert M, Brochez L (2012) Indoleamine 2,3-dioxygenase, a new prognostic marker in sentinel lymph nodes of melanoma patients. Eur J Cancer 48:2004–2011PubMed CrossRef
  162.Pollari S, Kakonen SM, Edgren H, Wolf M, Kohonen P, Sara H, Guise T, Nees M, Kallioniemi O (2011) Enhanced serine production by bone metastatic breast cancer cells stimulates osteoclastogenesis. Breast Cancer Res Treat 125:421–430PubMed CrossRef
  163.Sonveaux P, Vegran F, Schroeder T, Wergin MC, Verrax J, Rabbani ZN, De Saedeleer CJ, Kennedy KM, Diepart C, Jordan BF, Kelley MJ, Gallez B, Wahl ML, Feron O, Dewhirst MW (2008) Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Invest 118:3930–3942PubMed PubMedCentral
  164.Pavlides S, Whitaker-Menezes D, Castello-Cros R, Flomenberg N, Witkiewicz AK, Frank PG, Casimiro MC, Wang C, Fortina P, Addya S, Pestell RG, Martinez-Outschoorn UE, Sotgia F, Lisanti MP (2009) The reverse Warburg effect: aerobic glycolysis in cancer associated fibroblasts and the tumor stroma. Cell Cycle 8:3984–4001PubMed CrossRef
  165.Fiaschi T, Marini A, Giannoni E, Taddei ML, Gandellini P, De DA, Lanciotti M, Serni S, Cirri P, Chiarugi P (2012) Reciprocal metabolic reprogramming through lactate shuttle coordinately influences tumor-stroma interplay. Cancer Res 72:5130–5140PubMed CrossRef
  166.Giannoni E, Taddei ML, Morandi A, Comito G, Calvani M, Bianchini F, Richichi B, Raugei G, Wong N, Tang D, Chiarugi P (2015) Targeting stromal-induced pyruvate kinase M2 nuclear translocation impairs oxphos and prostate cancer metastatic spread. Oncotarget. PMID:26183399
  
• 作者单位：Paolo E. Porporato (1)
  Valéry L. Payen (1)
  Bjorn Baselet (1) (2)
  Pierre Sonveaux (1)
  
  1. Pole of Pharmacology, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCL), Avenue Emmanuel Mounier 52, box B1.53.09, 1200, Brussels, Belgium
  2. Radiobiology Unit, Belgian Nuclear Research Centre, SCK·CEN, 2400 Mol, Belgium
  
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Life Sciences
  Cell Biology
  Biomedicine
  Life Sciences
  Biochemistry
  
• 出版者：Birkh盲user Basel
• ISSN：1420-9071

文摘

Metabolic alterations are a hallmark of cancer controlling tumor progression and metastasis. Among the various metabolic phenotypes encountered in tumors, this review focuses on the contributions of mitochondria, lipid and amino acid metabolism to the metastatic process. Tumor cells require functional mitochondria to grow, proliferate and metastasize, but shifts in mitochondrial activities confer pro-metastatic traits encompassing increased production of mitochondrial reactive oxygen species (mtROS), enhanced resistance to apoptosis and the increased or de novo production of metabolic intermediates of the TCA cycle behaving as oncometabolites, including succinate, fumarate, and d-2-hydroxyglutarate that control energy production, biosynthesis and the redox state. Lipid metabolism and the metabolism of amino acids, such as glutamine, glutamate and proline are also currently emerging as focal control points of cancer metastasis.