Warburg's metabolic hypothesis is based on the assumption that a cancer cell's respiration must be under attack, leading to its damage, in order to obtain increased glycolysis. Although this may not apply to all cancers, there is some evidence proving that primarily abnormally functioning mitochondrial complexes are indeed related to cancer development. Thus, mutations in complex II (succinate dehydrogenase (SDH)) lead to the formation of pheochromocytoma (PHEO)/paraganglioma (PGL). Mutations in one of the SDH genes (SDHx mutations) lead to succinate accumulation associated with very low fumarate levels, increased glutaminolysis, the generation of reactive oxygen species, and pseudohypoxia. This results in significant changes in signaling pathways (many of them dependent on the stabilization of hypoxia-inducible factor), including oxidative phosphorylation, glycolysis, specific expression profiles, as well as genomic instability and increased mutability resulting in tumor development. Although there is currently no very effective therapy for SDHx-related metastatic PHEOs/PGLs, targeting their fundamental metabolic abnormalities may provide a unique opportunity for the development of novel and more effective forms of therapy for these tumors.

Department of Pediatric Hematology and Oncology 2nd Medical School Charles University and University Hospital Motol Prague Czech Republic Service Central de Biophysique et de Médecine Nucléaire CERIMED Centre Hospitalo Universitaire Timone Marseille France Département d'Oncologie Moléculaire Centre de Recherche en Cancérologie de Marseille Marseille France Program in Reproductive and Adult Endocrinology Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health Building 10 CRC 1 East Room 1 3140 10 Center Drive MSC 1109 Bethesda Maryland 20892 1109 USA

Zobrazit více v PubMed

Abraham RT, Eng CH. A metabolic (re-)balancing act. Mol Cell. 2010;38:481–482. PubMed

Agger K, Christensen J, Cloos PA, Helin K. The emerging functions of histone demethylases. Curr Opin Genet Dev. 2008;18:159–168. PubMed

Alston CL, Davison JE, Meloni F, van der Westhuizen FH, He L, Hornig-Do HT, Peet AC, Gissen P, Goffrini P, Ferrero I, et al. Recessive germline SDHA and SDHB mutations causing leukodystrophy and isolated mitochondrial complex II deficiency. J Med Genet. 2012;49:569–577. PubMed PMC

Astuti D, Hart-Holden N, Latif F, Lalloo F, Black GC, Lim C, Moran A, Grossman AB, Hodgson SV, Freemont A, et al. Genetic analysis of mitochondrial complex II subunits SDHD, SDHB and SDHC in paraganglioma and phaeochromocytoma susceptibility. Clin Endocrinol (Oxf) 2003;59:728–733. PubMed

Astuti D, Latif F, Dallol A, Dahia PL, Douglas F, George E, Skoldberg F, Husebye ES, Eng C, Maher ER. Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J Hum Genet. 2001;69:49–54. PubMed PMC

Astuti D, Morris M, Krona C, Abel F, Gentle D, Martinsson T, Kogner P, Neumann HP, Voutilainen R, Eng C, et al. Investigation of the role of SDHB inactivation in sporadic phaeochromocytoma and neuroblastoma. Br J Cancer. 2004;91:1835–1841. PubMed PMC

Bardella C, Pollard PJ, Tomlinson I. SDH mutations in cancer. Biochim Biophys Acta. 2011 doi: 10.1016/j.bbabio.2011.07.003. PubMed DOI

Bayley JP, Devilee P, Taschner PE. The SDH mutation database: an online resource for succinate dehydrogenase sequence variants involved in pheochromocytoma, paraganglioma and mitochondrial complex II deficiency. BMC Med Genet. 2005;6:39. PubMed PMC

Bayley JP, van Minderhout I, Weiss MM, Jansen JC, Oomen PH, Menko FH, Pasini B, Ferrando B, Wong N, Alpert LC, et al. Mutation analysis of SDHB and SDHC: novel germline mutations in sporadic head and neck paraganglioma and familial paraganglioma and/or pheochromocytoma. BMC Med Genet. 2006;7:1. PubMed PMC

Baysal BE. On the association of succinate dehydrogenase mutations with hereditary paraganglioma. Trends Endocrinol Metab. 2003;14:453–459. PubMed

Baysal BE. Genomic imprinting and environment in hereditary paraganglioma. Am J Med Genet C Semin Med Genet. 2004;129C:85–90. PubMed

Baysal BE. Clinical and molecular progress in hereditary paraganglioma. J Med Genet. 2008;45:689–694. PubMed

Baysal BE, Ferrell RE, Willett-Brozick JE, Lawrence EC, Myssiorek D, Bosch A, van der Mey A, Taschner PE, Rubinstein WS, Myers EN, et al. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science. 2000;287:848–851. PubMed

Benn DE, Gimenez-Roqueplo AP, Reilly JR, Bertherat J, Burgess J, Byth K, Croxson M, Dahia PL, Elston M, Gimm O, et al. Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. J Clin Endocrinol Metab. 2006;91:827–836. PubMed

Bensinger SJ, Christofk HR. New aspects of the Warburg effect in cancer cell biology. Semin Cell Dev Biol. 2012;23:352–361. PubMed

Birch-Machin MA, Taylor RW, Cochran B, Ackrell BA, Turnbull DM. Late-onset optic atrophy, ataxia, and myopathy associated with a mutation of a complex II gene. Ann Neurol. 2000;48:330–335. PubMed

Branco-Price C, Zhang N, Schnelle M, Evans C, Katschinski DM, Liao D, Ellies L, Johnson RS. Endothelial cell HIF-1alpha and HIF-2alpha differentially regulate metastatic success. Cancer Cell. 2012;21:52–65. PubMed PMC

Burnichon N, Briere JJ, Libe R, Vescovo L, Riviere J, Tissier F, Jouanno E, Jeunemaitre X, Benit P, Tzagoloff A, et al. SDHA is a tumor suppressor gene causing paraganglioma. Hum Mol Genet. 2010;19:3011–3020. PubMed PMC

Burnichon N, Buffet A, Parfait B, Letouze E, Laurendeau I, Loriot C, Pasmant E, Abermil N, Valeyrie-Allanore L, Bertherat J, et al. Somatic NF1 inactivation is a frequent event in sporadic pheochromocytoma. Hum Mol Genet. 2012a;21:5397–5405. PubMed

Burnichon N, Cascon A, Schiavi F, Morales NP, Comino-Mendez I, Abermil N, Inglada-Perez L, de Cubas AA, Amar L, Barontini M, et al. MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma. Clin Cancer Res. 2012b;18:2828–2837. PubMed

Burnichon N, Rohmer V, Amar L, Herman P, Leboulleux S, Darrouzet V, Niccoli P, Gaillard D, Chabrier G, Chabolle F, et al. The succinate dehydrogenase genetic testing in a large prospective series of patients with paragangliomas. J Clin Endocrinol Metab. 2009;94:2817–2827. PubMed

Burnichon N, Vescovo L, Amar L, Libe R, de Reynies A, Venisse A, Jouanno E, Laurendeau I, Parfait B, Bertherat J, et al. Integrative genomic analysis reveals somatic mutations in pheochromocytoma and paraganglioma. Hum Mol Genet. 2011;20:3974–3985. PubMed

Cairns RA, Harris IS, Mak TW. Regulation of cancer cell metabolism. Nat Rev Cancer. 2011;11:85–95. PubMed

Cardaci S, Desideri E, Ciriolo MR. Targeting aerobic glycolysis: 3-bromopyruvate as a promising anticancer drug. J Bioenerg Biomembr. 2012;44:17–29. PubMed

Cascon A, Landa I, Lopez-Jimenez E, Diez-Hernandez A, Buchta M, Montero-Conde C, Leskela S, Leandro-Garcia LJ, Leton R, Rodriguez-Antona C, et al. Molecular characterisation of a common SDHB deletion in paraganglioma patients. J Med Genet. 2008;45:233–238. PubMed

Cascon A, Tennant DA. From transcriptional profiling to tumor biology in pheochromocytoma and paraganglioma. Endocr Pathol. 2012;23:15–20. PubMed

Castro-Vega LJ, Buffet A, de Cubas AA, Cascon A, Menara M, Khalifa E, Amar L, Azriel S, Bourdeau I, Chabre O, et al. Germline mutations in FH confer predisposition to malignant pheochromocytomas and paragangliomas. Hum Mol Genet 2013 PubMed

Cervera AM, Bayley JP, Devilee P, McCreath KJ. Inhibition of succinate dehydrogenase dysregulates histone modification in mammalian cells. Mol Cancer. 2009;8:89. PubMed PMC

Chan DA, Sutphin PD, Nguyen P, Turcotte S, Lai EW, Banh A, Reynolds GE, Chi JT, Wu J, Solow-Cordero DE, et al. Targeting GLUT1 and the Warburg effect in renal cell carcinoma by chemical synthetic lethality. Sci Transl Med. 2011;3:94ra70. PubMed PMC

Chiavarina B, Martinez-Outschoorn UE, Whitaker-Menezes D, Howell A, Tanowitz HB, Pestell RG, Sotgia F, Lisanti MP. Metabolic reprogramming and two-compartment tumor metabolism: opposing role(s) of HIF1alpha and HIF2alpha in tumor-associated fibroblasts and human breast cancer cells. Cell Cycle. 2012;11:3280–3289. PubMed PMC

Chiche J, Brahimi-Horn MC, Pouyssegur J. Tumour hypoxia induces a metabolic shift causing acidosis: a common feature in cancer. J Cell Mol Med. 2010;14:771–794. PubMed PMC

Choi HJ, Song BJ, Gong YD, Gwak WJ, Soh Y. Rapid degradation of hypoxia-inducible factor-1alpha by KRH102053, a new activator of prolyl hydroxylase 2. Br J Pharmacol. 2008;154:114–125. PubMed PMC

Choi J, Jung WH, Koo JS. Metabolism-related proteins are differentially expressed according to the molecular subtype of invasive breast cancer defined by surrogate immunohistochemistry. Pathobiology. 2013;80:41–52. PubMed

Choo AY, Kim SG, Vander Heiden MG, Mahoney SJ, Vu H, Yoon SO, Cantley LC, Blenis J. Glucose addiction of TSC null cells is caused by failed mTORC1-dependent balancing of metabolic demand with supply. Mol Cell. 2010;38:487–499. PubMed PMC

Comino-Mendez I, Gracia-Aznarez FJ, Schiavi F, Landa I, Leandro-Garcia LJ, Leton R, Honrado E, Ramos-Medina R, Caronia D, Pita G, et al. Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma. Nat Genet. 2011;43:663–667. PubMed

Crona J, Delgado Verdugo A, Maharjan R, Stalberg P, Granberg D, Hellman P, Bjorklund P. Somatic mutations in H-RAS in sporadic pheochromocytoma and paraganglioma identified by exome sequencing. J Clin Endocrinol Metab. 2013;98:E1266–1271. PubMed

Dahia PL. The genetic landscape of pheochromocytomas and paragangliomas: somatic mutations take center stage. J Clin Endocrinol Metab. 2013;98:2679–2681. PubMed

Dahia PL, Ross KN, Wright ME, Hayashida CY, Santagata S, Barontini M, Kung AL, Sanso G, Powers JF, Tischler AS, et al. A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas. PLoS Genet. 2005;1:72–80. PubMed PMC

Dang CV. Glutaminolysis: supplying carbon or nitrogen or both for cancer cells? Cell Cycle. 2010;9:3884–3886. PubMed

Dang CV, Lewis BC, Dolde C, Dang G, Shim H. Oncogenes in tumor metabolism, tumorigenesis, and apoptosis. J Bioenerg Biomembr. 1997;29:345–354. PubMed

Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, Fantin VR, Jang HG, Jin S, Keenan MC, et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2009;462:739–744. PubMed PMC

Dann CE, 3rd, Bruick RK. Dioxygenases as O2-dependent regulators of the hypoxic response pathway. Biochem Biophys Res Commun. 2005;338:639–647. PubMed

Deberardinis RJ, Sayed N, Ditsworth D, Thompson CB. Brick by brick: metabolism and tumor cell growth. Curr Opin Genet Dev. 2008;18:54–61. PubMed PMC

Dudkina NV, Eubel H, Keegstra W, Boekema EJ, Braun HP. Structure of a mitochondrial supercomplex formed by respiratory-chain complexes I and III. Proc Natl Acad Sci U S A. 2005;102:3225–3229. PubMed PMC

Eakin RT, Morgan LO, Gregg CT, Matwiyoff NA. Carbon-13 nuclear magnetic resonance spectroscopy of living cells and their metabolism of a specifically labeled 13C substrate. FEBS Lett. 1972;28:259–264. PubMed

Eisenhofer G, Huynh TT, Pacak K, Brouwers FM, Walther MM, Linehan WM, Munson PJ, Mannelli M, Goldstein DS, Elkahloun AG. Distinct gene expression profiles in norepinephrine- and epinephrine-producing hereditary and sporadic pheochromocytomas: activation of hypoxia-driven angiogenic pathways in von Hippel-Lindau syndrome. Endocr Relat Cancer. 2004;11:897–911. PubMed

Eisenhofer G, Lenders JW, Siegert G, Bornstein SR, Friberg P, Milosevic D, Mannelli M, Linehan WM, Adams K, Timmers HJ, et al. Plasma methoxytyramine: a novel biomarker of metastatic pheochromocytoma and paraganglioma in relation to established risk factors of tumour size, location and SDHB mutation status. Eur J Cancer. 2012;48:1739–1749. PubMed PMC

Eisenhofer G, Lenders JW, Timmers H, Mannelli M, Grebe SK, Hofbauer LC, Bornstein SR, Tiebel O, Adams K, Bratslavsky G, et al. Measurements of plasma methoxytyramine, normetanephrine, and metanephrine as discriminators of different hereditary forms of pheochromocytoma. Clin Chem. 2011a;57:411–420. PubMed PMC

Eisenhofer G, Pacak K, Huynh TT, Qin N, Bratslavsky G, Linehan WM, Mannelli M, Friberg P, Grebe SK, Timmers HJ, et al. Catecholamine metabolomic and secretory phenotypes in phaeochromocytoma. Endocr Relat Cancer. 2011b;18:97–111. PubMed PMC

El Sayed SM, El-Magd RM, Shishido Y, Chung SP, Diem TH, Sakai T, Watanabe H, Kagami S, Fukui K. 3-Bromopyruvate antagonizes effects of lactate and pyruvate, synergizes with citrate and exerts novel anti-glioma effects. J Bioenerg Biomembr. 2012;44:61–79. PubMed

Eltzschig HK, Eckle T, Grenz A. PHD2 mutation and congenital erythrocytosis with paraganglioma. N Engl J Med. 2009;360:1361–1362. author reply 1362. PubMed

Eng C, Kiuru M, Fernandez MJ, Aaltonen LA. A role for mitochondrial enzymes in inherited neoplasia and beyond. Nat Rev Cancer. 2003;3:193–202. PubMed

Eng CH, Abraham RT. Glutaminolysis yields a metabolic by-product that stimulates autophagy. Autophagy. 2010;6:968–970. PubMed PMC

Erlic Z, Rybicki L, Peczkowska M, Golcher H, Kann PH, Brauckhoff M, Mussig K, Muresan M, Schaffler A, Reisch N, et al. Clinical predictors and algorithm for the genetic diagnosis of pheochromocytoma patients. Clin Cancer Res. 2009;15:6378–6385. PubMed

Fantin VR, St-Pierre J, Leder P. Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell. 2006;9:425–434. PubMed

Favier J, Briere JJ, Burnichon N, Riviere J, Vescovo L, Benit P, Giscos-Douriez I, De Reynies A, Bertherat J, Badoual C, et al. The Warburg effect is genetically determined in inherited pheochromocytomas. PLoS One. 2009;4:e7094. PubMed PMC

Favier J, Gimenez-Roqueplo AP. Pheochromocytomas: the (pseudo)-hypoxia hypothesis. Best Pract Res Clin Endocrinol Metab. 2010;24:957–968. PubMed

Favier J, Igaz P, Burnichon N, Amar L, Libe R, Badoual C, Tissier F, Bertherat J, Plouin PF, Jeunemaitre X, et al. Rationale for anti-angiogenic therapy in pheochromocytoma and paraganglioma. Endocr Pathol. 2012;23:34–42. PubMed

Favier J, Kempf H, Corvol P, Gasc JM. Cloning and expression pattern of EPAS1 in the chicken embryo. Colocalization with tyrosine hydroxylase. FEBS Lett. 1999;462:19–24. PubMed

Fliedner SMJ, Kaludercic N, Jiang X, Hansikova H, Hajkova Z, Sladkova J, Limpuangthip A, Backlund PS, Wesley R, Martiniova L, et al. Warburg Effect’s Manifestation in Aggressive Pheochromocytomas and Paragangliomas: Insights from a Mouse Cell Model Applied to Human Tumor Tissue. PlosOne. 2012 in press. PubMed PMC

Florczyk U, Czauderna S, Stachurska A, Tertil M, Nowak W, Kozakowska M, Poellinger L, Jozkowicz A, Loboda A, Dulak J. Opposite effects of HIF-1alpha and HIF-2alpha on the regulation of IL-8 expression in endothelial cells. Free Radic Biol Med. 2011;51:1882–1892. PubMed PMC

Franke K, Gassmann M, Wielockx B. Erythrocytosis: the HIF pathway in control. Blood. 2013;122:1122–1128. PubMed

Furlow PW, Percy MJ, Sutherland S, Bierl C, McMullin MF, Master SR, Lappin TR, Lee FS. Erythrocytosis-associated HIF-2alpha mutations demonstrate a critical role for residues C-terminal to the hydroxylacceptor proline. J Biol Chem. 2009;284:9050–9058. PubMed PMC

Gaal J, Burnichon N, Korpershoek E, Roncelin I, Bertherat J, Plouin PF, de Krijger RR, Gimenez-Roqueplo AP, Dinjens WN. Isocitrate dehydrogenase mutations are rare in pheochromocytomas and paragangliomas. J Clin Endocrinol Metab. 2010;95:1274–1278. PubMed

Galan SR, Kann PH. Genetics and molecular pathogenesis of pheochromocytoma and paraganglioma. Clin Endocrinol (Oxf) 2013;78:165–175. PubMed

Gao P, Zhang H, Dinavahi R, Li F, Xiang Y, Raman V, Bhujwalla ZM, Felsher DW, Cheng L, Pevsner J, et al. HIF-dependent antitumorigenic effect of antioxidants in vivo. Cancer Cell. 2007;12:230–238. PubMed PMC

Gatenby RA, Gillies RJ. Why do cancers have high aerobic glycolysis? Nat Rev Cancer. 2004;4:891–899. PubMed

Ghayee HK, Giubellino A, Click A, Kapur P, Christie A, Xie XJ, Martucci V, Shay JW, Souza RF, Pacak K. Phospho-mTOR is not upregulated in metastatic SDHB paragangliomas. Eur J Clin Invest. 2013;43:970–977. PubMed PMC

Gill AJ, Pachter NS, Clarkson A, Tucker KM, Winship IM, Benn DE, Robinson BG, Clifton-Bligh RJ. Renal tumors and hereditary pheochromocytoma-paraganglioma syndrome type 4. N Engl J Med. 2011;364:885–886. PubMed

Gimenez-Roqueplo AP, Dahia PL, Robledo M. An update on the genetics of paraganglioma, pheochromocytoma, and associated hereditary syndromes. Horm Metab Res. 2012;44:328–333. PubMed

Gimenez-Roqueplo AP, Favier J, Rustin P, Mourad JJ, Plouin PF, Corvol P, Rotig A, Jeunemaitre X. The R22X mutation of the SDHD gene in hereditary paraganglioma abolishes the enzymatic activity of complex II in the mitochondrial respiratory chain and activates the hypoxia pathway. Am J Hum Genet. 2001;69:1186–1197. PubMed PMC

Gimenez-Roqueplo AP, Favier J, Rustin P, Rieubland C, Crespin M, Nau V, Khau Van Kien P, Corvol P, Plouin PF, Jeunemaitre X. Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas. Cancer Res. 2003;63:5615–5621. PubMed

Gimenez-Roqueplo AP, Favier J, Rustin P, Rieubland C, Kerlan V, Plouin PF, Rotig A, Jeunemaitre X. Functional consequences of a SDHB gene mutation in an apparently sporadic pheochromocytoma. J Clin Endocrinol Metab. 2002;87:4771–4774. PubMed

Giubellino A, Sourbier C, Lee MJ, Scroggins B, Bullova P, Landau M, Ying W, Neckers L, Trepel JB, Pacak K. Targeting heat shock protein 90 for the treatment of malignant pheochromocytoma. PLoS One. 2013;8:e56083. PubMed PMC

Goffrini P, Ercolino T, Panizza E, Giache V, Cavone L, Chiarugi A, Dima V, Ferrero I, Mannelli M. Functional study in a yeast model of a novel succinate dehydrogenase subunit B gene germline missense mutation (C191Y) diagnosed in a patient affected by a glomus tumor. Hum Mol Genet. 2009;18:1860–1868. PubMed

Gogvadze V, Zhivotovsky B, Orrenius S. The Warburg effect and mitochondrial stability in cancer cells. Mol Aspects Med. 2010;31:60–74. PubMed

Gottlieb E, Tomlinson IP. Mitochondrial tumour suppressors: a genetic and biochemical update. Nat Rev Cancer. 2005;5:857–866. PubMed

Guzy RD, Sharma B, Bell E, Chandel NS, Schumacker PT. Loss of the SdhB, but Not the SdhA, subunit of complex II triggers reactive oxygen species-dependent hypoxia-inducible factor activation and tumorigenesis. Mol Cell Biol. 2008;28:718–731. PubMed PMC

Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70. PubMed

Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–674. PubMed

Hao HX, Khalimonchuk O, Schraders M, Dephoure N, Bayley JP, Kunst H, Devilee P, Cremers CW, Schiffman JD, Bentz BG, et al. SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science. 2009;325:1139–1142. PubMed PMC

Hewitson KS, McNeill LA, Elkins JM, Schofield CJ. The role of iron and 2-oxoglutarate oxygenases in signalling. Biochem Soc Trans. 2003;31:510–515. PubMed

Hobert JA, Mester JL, Moline J, Eng C. Elevated plasma succinate in PTEN, SDHB, and SDHD mutation-positive individuals. Genet Med. 2012;14:616–619. PubMed PMC

Holmquist-Mengelbier L, Fredlund E, Lofstedt T, Noguera R, Navarro S, Nilsson H, Pietras A, Vallon-Christersson J, Borg A, Gradin K, et al. Recruitment of HIF-1alpha and HIF-2alpha to common target genes is differentially regulated in neuroblastoma: HIF-2alpha promotes an aggressive phenotype. Cancer Cell. 2006;10:413–423. PubMed

Horvath R, Abicht A, Holinski-Feder E, Laner A, Gempel K, Prokisch H, Lochmuller H, Klopstock T, Jaksch M. Leigh syndrome caused by mutations in the flavoprotein (Fp) subunit of succinate dehydrogenase (SDHA) J Neurol Neurosurg Psychiatry. 2006;77:74–76. PubMed PMC

Huang J, Lemire BD. Mutations in the C. elegans succinate dehydrogenase iron-sulfur subunit promote superoxide generation and premature aging. J Mol Biol. 2009;387:559–569. PubMed

Imperiale A, Moussallieh FM, Sebag F, Brunaud L, Barlier A, Elbayed K, Bachellier P, Goichot B, Pacak K, Namer IJ, et al. A new specific succinate-glutamate metabolomic hallmark in sdhx-related paragangliomas. PLoS One. 2013;8:e80539. PubMed PMC

Isaacs JS, Jung YJ, Mimnaugh EG, Martinez A, Cuttitta F, Neckers LM. Hsp90 regulates a von Hippel Lindau-independent hypoxia-inducible factor-1 alpha-degradative pathway. J Biol Chem. 2002;277:29936–29944. PubMed

Isaacs JS, Jung YJ, Mole DR, Lee S, Torres-Cabala C, Chung YL, Merino M, Trepel J, Zbar B, Toro J, 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. 2005;8:143–153. PubMed

Jiang H, Zhang L, Koubi D, Kuo J, Groc L, Rodriguez AI, Hunter TJ, Tang S, Lazarovici P, Gautam SC, et al. Roles of Ras-Erk in apoptosis of PC12 cells induced by trophic factor withdrawal or oxidative stress. J Mol Neurosci. 2005;25:133–140. PubMed

Jiang S, Dahia PL. Minireview: the busy road to pheochromocytomas and paragangliomas has a new member, TMEM127. Endocrinology. 2011;152:2133–2140. PubMed

Jochmanova I, Yang C, Zhuang Z, Pacak K. Hypoxia-inducible factor signaling in pheochromocytoma: turning the rudder in the right direction. J Natl Cancer Inst. 2013;105:1270–1283. PubMed PMC

Jokilehto T, Jaakkola PM. The role of HIF prolyl hydroxylases in tumour growth. J Cell Mol Med. 2010;14:758–770. PubMed PMC

Jones RG, Thompson CB. Tumor suppressors and cell metabolism: a recipe for cancer growth. Genes Dev. 2009;23:537–548. PubMed PMC

Kaelin WG, Jr, McKnight SL. Influence of metabolism on epigenetics and disease. Cell. 2013;153:56–69. PubMed PMC

Kaelin WG, Jr, Ratcliffe PJ. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell. 2008;30:393–402. PubMed

Keith B, Johnson RS, Simon MC. HIF1alpha and HIF2alpha: sibling rivalry in hypoxic tumour growth and progression. Nat Rev Cancer. 2012;12:9–22. PubMed PMC

Khan MN, Bhattacharyya T, Andrikopoulos P, Esteban MA, Barod R, Connor T, Ashcroft M, Maxwell PH, Kiriakidis S. Factor inhibiting HIF (FIH-1) promotes renal cancer cell survival by protecting cells from HIF-1alpha-mediated apoptosis. Br J Cancer. 2011;104:1151–1159. PubMed PMC

Killian JK, Kim SY, Miettinen M, Smith C, Merino M, Tsokos M, Quezado M, Smith WI, Jr, Jahromi MS, Xekouki P, et al. Succinate dehydrogenase mutation underlies global epigenomic divergence in gastrointestinal stromal tumor. Cancer Discov. 2013;3:648–657. PubMed PMC

King A, Selak MA, Gottlieb E. Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer. Oncogene. 2006;25:4675–4682. PubMed

Kluza J, Corazao-Rozas P, Touil Y, Jendoubi M, Maire C, Guerreschi P, Jonneaux A, Ballot C, Balayssac S, Valable S, et al. Inactivation of the HIF-1alpha/PDK3 Signaling Axis Drives Melanoma toward Mitochondrial Oxidative Metabolism and Potentiates the Therapeutic Activity of Pro-Oxidants. Cancer Res. 2012;72:5035–5047. PubMed

Koh MY, Lemos R, Jr, Liu X, Powis G. The hypoxia-associated factor switches cells from HIF-1alpha- to HIF-2alpha-dependent signaling promoting stem cell characteristics, aggressive tumor growth and invasion. Cancer Res. 2011;71:4015–4027. PubMed PMC

Koppenol WH, Bounds PL, Dang CV. Otto Warburg’s contributions to current concepts of cancer metabolism. Nat Rev Cancer. 2011;11:325–337. PubMed

Korpershoek E, Favier J, Gaal J, Burnichon N, van Gessel B, Oudijk L, Badoual C, Gadessaud N, Venisse A, Bayley JP, et al. SDHA immunohistochemistry detects germline SDHA gene mutations in apparently sporadic paragangliomas and pheochromocytomas. J Clin Endocrinol Metab. 2011;96:E1472–1476. PubMed

Krejci A. Metabolic sensors and their interplay with cell signalling and transcription. Biochem Soc Trans. 2012;40:311–323. PubMed

Kumar A, Kant S, Singh SM. 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. 2012;199:29–37. PubMed

Ladroue C, Carcenac R, Leporrier M, Gad S, Le Hello C, Galateau-Salle F, Feunteun J, Pouyssegur J, Richard S, Gardie B. PHD2 mutation and congenital erythrocytosis with paraganglioma. N Engl J Med. 2008;359:2685–2692. PubMed

Lando D, Peet DJ, Gorman JJ, Whelan DA, Whitelaw ML, Bruick RK. FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes Dev. 2002;16:1466–1471. PubMed PMC

Latif F, Duh FM, Gnarra J, Tory K, Kuzmin I, Yao M, Stackhouse T, Modi W, Geil L, Schmidt L, et al. von Hippel-Lindau syndrome: cloning and identification of the plasma membrane Ca(++)-transporting ATPase isoform 2 gene that resides in the von Hippel-Lindau gene region. Cancer Res. 1993;53:861–867. PubMed

Lee S, Nakamura E, Yang H, Wei W, Linggi MS, Sajan MP, Farese RV, Freeman RS, Carter BD, Kaelin WG, Jr, et al. Neuronal apoptosis linked to EglN3 prolyl hydroxylase and familial pheochromocytoma genes: developmental culling and cancer. Cancer Cell. 2005;8:155–167. PubMed

Lenders JW, Eisenhofer G, Mannelli M, Pacak K. Phaeochromocytoma. Lancet. 2005;366:665–675. PubMed

Lendvai N, Pawlosky R, Bullova P, Eisenhofer G, Patocs A, Veech RL, Pacak K. Succinate-to-Fumarate Ratio as a New Metabolic Marker to Detect the Presence of SDHB/D-related Paraganglioma: Initial Experimental and Ex Vivo Findings. Endocrinology 2013 PubMed PMC

Letouze E, Martinelli C, Loriot C, Burnichon N, Abermil N, Ottolenghi C, Janin M, Menara M, Nguyen AT, Benit P, et al. SDH Mutations Establish a Hypermethylator Phenotype in Paraganglioma. Cancer Cell. 2013;23:739–752. PubMed

Levine AJ, Puzio-Kuter AM. The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes. Science. 2010;330:1340–1344. PubMed

Levitas A, Muhammad E, Harel G, Saada A, Caspi VC, Manor E, Beck JC, Sheffield V, Parvari R. Familial neonatal isolated cardiomyopathy caused by a mutation in the flavoprotein subunit of succinate dehydrogenase. Eur J Hum Genet. 2010;18:1160–1165. PubMed PMC

Linehan WM, Rouault TA. Molecular pathways: fumarate hydratase-deficient kidney cancer--targeting the warburg effect in cancer. Clin Cancer Res. 2013;19:3345–3352. PubMed PMC

Liu Y, Cao Y, Zhang W, Bergmeier S, Qian Y, Akbar H, Colvin R, Ding J, Tong L, Wu S, 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. 2012;11:1672–1682. PubMed

Liu YV, Baek JH, Zhang H, Diez R, Cole RN, Semenza GL. RACK1 competes with HSP90 for binding to HIF-1alpha and is required for O(2)-independent and HSP90 inhibitor-induced degradation of HIF-1alpha. Mol Cell. 2007;25:207–217. PubMed PMC

Lopez-Jimenez E, Gomez-Lopez G, Leandro-Garcia LJ, Munoz I, Schiavi F, Montero-Conde C, de Cubas AA, Ramires R, Landa I, Leskela S, et al. Research resource: Transcriptional profiling reveals different pseudohypoxic signatures in SDHB and VHL-related pheochromocytomas. Mol Endocrinol. 2010;24:2382–2391. PubMed PMC

Lorenzo FR, Yang C, Ng Tang Fui M, Vankayalapati H, Zhuang Z, Huynh T, Grossmann M, Pacak K, Prchal JT. A novel EPAS1/HIF2A germline mutation in a congenital polycythemia with paraganglioma. J Mol Med (Berl) 2012 PubMed PMC

Luo W, Hu H, Chang R, Zhong J, Knabel M, O’Meally R, Cole RN, Pandey A, Semenza GL. Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell. 2011;145:732–744. PubMed PMC

Luo W, Semenza GL. Pyruvate kinase M2 regulates glucose metabolism by functioning as a coactivator for hypoxia-inducible factor 1 in cancer cells. Oncotarget. 2011;2:551–556. PubMed PMC

Luo W, Semenza GL. Emerging roles of PKM2 in cell metabolism and cancer progression. Trends Endocrinol Metab. 2012;23:560–566. PubMed PMC

MacKenzie ED, Selak MA, Tennant DA, Payne LJ, Crosby S, Frederiksen CM, Watson DG, Gottlieb E. Cell-permeating alpha-ketoglutarate derivatives alleviate pseudohypoxia in succinate dehydrogenase-deficient cells. Mol Cell Biol. 2007;27:3282–3289. PubMed PMC

Mahalingam D, Swords R, Carew JS, Nawrocki ST, Bhalla K, Giles FJ. Targeting HSP90 for cancer therapy. Br J Cancer. 2009;100:1523–1529. PubMed PMC

Maher ER, Eng C. The pressure rises: update on the genetics of phaeochromocytoma. Hum Mol Genet. 2002;11:2347–2354. PubMed

Mahon PC, Hirota K, Semenza GL. FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity. Genes Dev. 2001;15:2675–2686. PubMed PMC

Majmundar AJ, Wong WJ, Simon MC. Hypoxia-inducible factors and the response to hypoxic stress. Mol Cell. 2010;40:294–309. PubMed PMC

Mathupala SP, Ko YH, Pedersen PL. Hexokinase-2 bound to mitochondria: cancer’s stygian link to the “Warburg Effect” and a pivotal target for effective therapy. Semin Cancer Biol. 2009;19:17–24. PubMed PMC

Matsushita K, Uchida K, Saigusa S, Ide S, Hashimoto K, Koike Y, Otake K, Inoue M, Tanaka K, Kusunoki M. Glycolysis inhibitors as a potential therapeutic option to treat aggressive neuroblastoma expressing GLUT1. J Pediatr Surg. 2012;47:1323–1330. PubMed

Meng M, Chen S, Lao T, Liang D, Sang N. Nitrogen anabolism underlies the importance of glutaminolysis in proliferating cells. Cell Cycle. 2010;9:3921–3932. PubMed PMC

Michelakis ED, Webster L, Mackey JR. Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer. Br J Cancer. 2008;99:989–994. PubMed PMC

Mole DR, Blancher C, Copley RR, Pollard PJ, Gleadle JM, Ragoussis J, Ratcliffe PJ. Genome-wide association of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha DNA binding with expression profiling of hypoxia-inducible transcripts. J Biol Chem. 2009;284:16767–16775. PubMed PMC

Mulligan LM, Kwok JB, Healey CS, Elsdon MJ, Eng C, Gardner E, Love DR, Mole SE, Moore JK, Papi L, et al. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature. 1993;363:458–460. PubMed

Nakajima EC, Van Houten B. Metabolic symbiosis in cancer: Refocusing the Warburg lens. Mol Carcinog 2012 PubMed PMC

Nepal M, Gong YD, Park YR, Soh Y. An activator of PHD2, KRH102140, decreases angiogenesis via inhibition of HIF-1alpha. Cell Biochem Funct. 2011;29:126–134. PubMed

Neumann HP, Bausch B, McWhinney SR, Bender BU, Gimm O, Franke G, Schipper J, Klisch J, Altehoefer C, Zerres K, et al. Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med. 2002;346:1459–1466. PubMed

Ni Y, Eng C. Vitamin E Protects against Lipid Peroxidation and Rescues Tumorigenic Phenotypes in Cowden/Cowden-like Patient-derived Lymphoblast Cells with Germline SDHx Variants. Clin Cancer Res 2012 PubMed PMC

Ni Y, He X, Chen J, Moline J, Mester J, Orloff MS, Ringel MD, Eng C. Germline SDHx variants modify breast and thyroid cancer risks in Cowden and Cowden-like syndrome via FAD/NAD-dependant destabilization of p53. Hum Mol Genet. 2012;21:300–310. PubMed PMC

Ni Y, Zbuk KM, Sadler T, Patocs A, Lobo G, Edelman E, Platzer P, Orloff MS, Waite KA, Eng C. Germline mutations and variants in the succinate dehydrogenase genes in Cowden and Cowden-like syndromes. Am J Hum Genet. 2008;83:261–268. PubMed PMC

Niemann S, Muller U. Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nat Genet. 2000;26:268–270. PubMed

Nilsson H, Jogi A, Beckman S, Harris AL, Poellinger L, Pahlman S. HIF-2alpha expression in human fetal paraganglia and neuroblastoma: relation to sympathetic differentiation, glucose deficiency, and hypoxia. Exp Cell Res. 2005;303:447–456. PubMed

Nolting S, Garcia E, Alusi G, Giubellino A, Pacak K, Korbonits M, Grossman AB. Combined blockade of signalling pathways shows marked anti-tumour potential in phaeochromocytoma cell lines. J Mol Endocrinol. 2012;49:79–96. PubMed PMC

Nolting S, Grossman AB. Signaling pathways in pheochromocytomas and paragangliomas: prospects for future therapies. Endocr Pathol. 2012;23:21–33. PubMed

Northcott PA, Shih DJ, Remke M, Cho YJ, Kool M, Hawkins C, Eberhart CG, Dubuc A, Guettouche T, Cardentey Y, et al. Rapid, reliable, and reproducible molecular subgrouping of clinical medulloblastoma samples. Acta Neuropathol. 2012;123:615–626. PubMed PMC

Osthus RC, Shim H, Kim S, Li Q, Reddy R, Mukherjee M, Xu Y, Wonsey D, Lee LA, Dang CV. Deregulation of glucose transporter 1 and glycolytic gene expression by c-Myc. J Biol Chem. 2000;275:21797–21800. PubMed

Owens KM, Aykin-Burns N, Dayal D, Coleman MC, Domann FE, Spitz DR. Genomic instability induced by mutant succinate dehydrogenase subunit D (SDHD) is mediated by O2(−*) and H2O2. Free Radic Biol Med. 2012;52:160–166. PubMed PMC

Pan JS, Hong MZ, Ren JL. Reactive oxygen species: a double-edged sword in oncogenesis. World J Gastroenterol. 2009;15:1702–1707. PubMed PMC

Papaspyrou K, Mewes T, Rossmann H, Fottner C, Schneider-Raetzke B, Bartsch O, Schreckenberger M, Lackner KJ, Amedee RG, Mann WJ. Head and neck paragangliomas: Report of 175 patients (1989–2010) Head Neck 2011 PubMed

Parfait B, Chretien D, Rotig A, Marsac C, Munnich A, Rustin P. Compound heterozygous mutations in the flavoprotein gene of the respiratory chain complex II in a patient with Leigh syndrome. Hum Genet. 2000;106:236–243. PubMed

Parks SK, Chiche J, Pouyssegur J. Disrupting proton dynamics and energy metabolism for cancer therapy. Nat Rev Cancer. 2013;13:611–623. PubMed

Patel SA, Simon MC. Biology of hypoxia-inducible factor-2alpha in development and disease. Cell Death Differ. 2008;15:628–634. PubMed PMC

Pedersen PL. 3-Bromopyruvate (3BP) a fast acting, promising, powerful, specific, and effective “small molecule” anti-cancer agent taken from labside to bedside: introduction to a special issue. J Bioenerg Biomembr. 2012;44:1–6. PubMed

Pollard PJ, Briere JJ, Alam NA, Barwell J, Barclay E, Wortham NC, Hunt T, Mitchell M, Olpin S, Moat SJ, et al. Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations. Hum Mol Genet. 2005;14:2231–2239. PubMed

Pollard PJ, El-Bahrawy M, Poulsom R, Elia G, Killick P, Kelly G, Hunt T, Jeffery R, Seedhar P, Barwell J, et al. Expression of HIF-1alpha, HIF-2alpha (EPAS1), and their target genes in paraganglioma and pheochromocytoma with VHL and SDH mutations. J Clin Endocrinol Metab. 2006;91:4593–4598. PubMed

Powers JF, Evinger MJ, Zhi J, Picard KL, Tischler AS. Pheochromocytomas in Nf1 knockout mice express a neural progenitor gene expression profile. Neuroscience. 2007;147:928–937. PubMed

Qin Y, Yao L, King EE, Buddavarapu K, Lenci RE, Chocron ES, Lechleiter JD, Sass M, Aronin N, Schiavi F, et al. Germline mutations in TMEM127 confer susceptibility to pheochromocytoma. Nat Genet. 2010;42:229–233. PubMed PMC

Rankin EB, Biju MP, Liu Q, Unger TL, Rha J, Johnson RS, Simon MC, Keith B, Haase VH. Hypoxia-inducible factor-2 (HIF-2) regulates hepatic erythropoietin in vivo. J Clin Invest. 2007;117:1068–1077. PubMed PMC

Rao JU, Engelke UF, Rodenburg RJ, Wevers RA, Pacak K, Eisenhofer G, Qin N, Kusters B, Goudswaard AG, Lenders JW, et al. Genotype-Specific Abnormalities in Mitochondrial Function Associate with Distinct Profiles of Energy Metabolism and Catecholamine Content in Pheochromocytoma and Paraganglioma. Clin Cancer Res. 2013;19:3787–3795. PubMed PMC

Rapizzi E, Ercolino T, Canu L, Giache V, Francalanci M, Pratesi C, Valeri A, Mannelli M. Mitochondrial function and content in pheochromocytoma/paraganglioma of succinate dehydrogenase mutation carriers. Endocr Relat Cancer. 2012;19:261–269. PubMed

Rogers JL, Bayeh L, Scheuermann TH, Longgood J, Key J, Naidoo J, Melito L, Shokri C, Frantz DE, Bruick RK, et al. Development of inhibitors of the PAS-B domain of the HIF-2alpha transcription factor. J Med Chem. 2013;56:1739–1747. PubMed PMC

Rustin P, Munnich A, Rotig A. Succinate dehydrogenase and human diseases: new insights into a well-known enzyme. Eur J Hum Genet. 2002;10:289–291. PubMed

Sandgren J, Diaz de Stahl T, Andersson R, Menzel U, Piotrowski A, Nord H, Backdahl M, Kiss NB, Brauckhoff M, Komorowski J, et al. Recurrent genomic alterations in benign and malignant pheochromocytomas and paragangliomas revealed by whole-genome array comparative genomic hybridization analysis. Endocr Relat Cancer. 2010;17:561–579. PubMed

Schiavi F, Boedeker CC, Bausch B, Peczkowska M, Gomez CF, Strassburg T, Pawlu C, Buchta M, Salzmann M, Hoffmann MM, et al. Predictors and prevalence of paraganglioma syndrome associated with mutations of the SDHC gene. JAMA. 2005;294:2057–2063. PubMed

Schlisio S, Kenchappa RS, Vredeveld LC, George RE, Stewart R, Greulich H, Shahriari K, Nguyen NV, Pigny P, Dahia PL, et al. The kinesin KIF1Bbeta acts downstream from EglN3 to induce apoptosis and is a potential 1p36 tumor suppressor. Genes Dev. 2008;22:884–893. PubMed PMC

Selak MA, Armour SM, MacKenzie ED, Boulahbel H, Watson DG, Mansfield KD, Pan Y, Simon MC, Thompson CB, Gottlieb E. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell. 2005;7:77–85. PubMed

Semenza G. Signal transduction to hypoxia-inducible factor 1. Biochem Pharmacol. 2002a;64:993–998. PubMed

Semenza GL. HIF-1 and tumor progression: pathophysiology and therapeutics. Trends Mol Med. 2002b;8:S62–67. PubMed

Semenza GL. Evaluation of HIF-1 inhibitors as anticancer agents. Drug Discov Today. 2007;12:853–859. PubMed

Semenza GL. Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene. 2010;29:625–634. PubMed PMC

Semenza GL. Oxygen sensing, homeostasis, and disease. N Engl J Med. 2011;365:537–547. PubMed

Semenza GL. Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy. Trends Pharmacol Sci. 2012;33:207–214. PubMed PMC

Shah U, Giubellino A, Pacak K. Pheochromocytoma: implications in tumorigenesis and the actual management. Minerva Endocrinol. 2012;37:141–156. PubMed PMC

Singh RP, Franke K, Kalucka J, Mamlouk S, Muschter A, Gembarska A, Grinenko T, Willam C, Naumann R, Anastassiadis K, et al. HIF prolyl hydroxylase 2 (PHD2) is a critical regulator of hematopoietic stem cell maintenance during steady-state and stress. Blood. 2013;121:5158–5166. PubMed

Slane BG, Aykin-Burns N, Smith BJ, Kalen AL, Goswami PC, Domann FE, Spitz DR. Mutation of succinate dehydrogenase subunit C results in increased O2.-, oxidative stress, and genomic instability. Cancer Res. 2006;66:7615–7620. PubMed

Soga T. Cancer metabolism: key players in metabolic reprogramming. Cancer Sci. 2013;104:275–281. PubMed PMC

Spitz DR. Metabolic oxidative stress and low dose radiation responses: are mitochondria involved. Health Phys. 2011;100:295. PubMed

Sun F, Huo X, Zhai Y, Wang A, Xu J, Su D, Bartlam M, Rao Z. Crystal structure of mitochondrial respiratory membrane protein complex II. Cell. 2005a;121:1043–1057. PubMed

Sun L, Bartlam M, Liu Y, Pang H, Rao Z. Crystal structure of the pyridoxal-5′-phosphate-dependent serine dehydratase from human liver. Protein Sci. 2005b;14:791–798. PubMed PMC

Sutendra G, Dromparis P, Kinnaird A, Stenson TH, Haromy A, Parker JM, McMurtry MS, Michelakis ED. Mitochondrial activation by inhibition of PDKII suppresses HIF1a signaling and angiogenesis in cancer. Oncogene. 2013;32:1638–1650. PubMed

Sutendra G, Michelakis ED. Pyruvate dehydrogenase kinase as a novel therapeutic target in oncology. Front Oncol. 2013;3:38. PubMed PMC

Taieb D, Sebag F, Barlier A, Tessonnier L, Palazzo FF, Morange I, Niccoli-Sire P, Fakhry N, De Micco C, Cammilleri S, et al. 18F-FDG avidity of pheochromocytomas and paragangliomas: a new molecular imaging signature? J Nucl Med. 2009;50:711–717. PubMed

Tannahill GM, Curtis AM, Adamik J, Palsson-McDermott EM, McGettrick AF, Goel G, Frezza C, Bernard NJ, Kelly B, Foley NH, et al. Succinate is an inflammatory signal that induces IL-1beta through HIF-1alpha. Nature. 2013;496:238–242. PubMed PMC

Tennant DA, Frezza C, MacKenzie ED, Nguyen QD, Zheng L, Selak MA, Roberts DL, Dive C, Watson DG, Aboagye EO, et al. Reactivating HIF prolyl hydroxylases under hypoxia results in metabolic catastrophe and cell death. Oncogene. 2009;28:4009–4021. PubMed

Tennant DA, Gottlieb E. HIF prolyl hydroxylase-3 mediates alpha-ketoglutarate-induced apoptosis and tumor suppression. J Mol Med (Berl) 2010;88:839–849. PubMed

Tian H, Hammer RE, Matsumoto AM, Russell DW, McKnight SL. The hypoxia-responsive transcription factor EPAS1 is essential for catecholamine homeostasis and protection against heart failure during embryonic development. Genes Dev. 1998;12:3320–3324. PubMed PMC

Timmers HJ, Chen CC, Carrasquillo JA, Whatley M, Ling A, Eisenhofer G, King KS, Rao JU, Wesley RA, Adams KT, et al. Staging and functional characterization of pheochromocytoma and paraganglioma by 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography. J Natl Cancer Inst. 2012;104:700–708. PubMed PMC

Timmers HJ, Chen CC, Carrasquillo JA, Whatley M, Ling A, Havekes B, Eisenhofer G, Martiniova L, Adams KT, Pacak K. Comparison of 18F-fluoro-L-DOPA, 18F-fluoro-deoxyglucose, and 18F-fluorodopamine PET and 123I-MIBG scintigraphy in the localization of pheochromocytoma and paraganglioma. J Clin Endocrinol Metab. 2009a;94:4757–4767. PubMed PMC

Timmers HJ, Gimenez-Roqueplo AP, Mannelli M, Pacak K. Clinical aspects of SDHx-related pheochromocytoma and paraganglioma. Endocr Relat Cancer. 2009b;16:391–400. PubMed PMC

Timmers HJ, Kozupa A, Eisenhofer G, Raygada M, Adams KT, Solis D, Lenders JW, Pacak K. Clinical presentations, biochemical phenotypes, and genotype-phenotype correlations in patients with succinate dehydrogenase subunit B-associated pheochromocytomas and paragangliomas. J Clin Endocrinol Metab. 2007;92:779–786. PubMed

Toledo RA, Qin Y, Srikantan S, Morales NP, Li Q, Deng Y, Kim SW, Pereira MA, Toledo SP, Su X, et al. In vivo and in vitro oncogenic effects of HIF2A mutations in pheochromocytomas and paragangliomas. Endocr Relat Cancer. 2013;20:349–359. PubMed PMC

van Nederveen FH, Gaal J, Favier J, Korpershoek E, Oldenburg RA, de Bruyn EM, Sleddens HF, Derkx P, Riviere J, Dannenberg H, et al. An immunohistochemical procedure to detect patients with paraganglioma and phaeochromocytoma with germline SDHB, SDHC, or SDHD gene mutations: a retrospective and prospective analysis. Lancet Oncol. 2009;10:764–771. PubMed PMC

Vegran F, Boidot R, Michiels C, Sonveaux P, Feron O. Lactate influx through the endothelial cell monocarboxylate transporter MCT1 supports an NF-kappaB/IL-8 pathway that drives tumor angiogenesis. Cancer Res. 2011;71:2550–2560. PubMed

Vicha A, Musil Z, Pacak K. Genetics of pheochromocytoma and paraganglioma syndromes: new advances and future treatment options. Curr Opin Endocrinol Diabetes Obes. 2013;20:186–191. PubMed PMC

Viskochil D, Buchberg AM, Xu G, Cawthon RM, Stevens J, Wolff RK, Culver M, Carey JC, Copeland NG, Jenkins NA, et al. Deletions and a translocation interrupt a cloned gene at the neurofibromatosis type 1 locus. Cell. 1990;62:187–192. PubMed

Vogelstein B, Kinzler KW. Cancer genes and the pathways they control. Nat Med. 2004;10:789–799. PubMed

Walenta S, Mueller-Klieser WF. Lactate: mirror and motor of tumor malignancy. Semin Radiat Oncol. 2004;14:267–274. PubMed

Warburg O. On the origin of cancer cells. Science. 1956;123:309–314. PubMed

Warburg O, Wind F, Negelein E. Über den Stoffwechsel der Tumoren in Körper. Klinische Wochenschrift. 1926:829–832.

Weber A, Hoffmann MM, Neumann HP, Erlic Z. Somatic Mutation Analysis of the SDHB, SDHC, SDHD, and RET Genes in the Clinical Assessment of Sporadic and Hereditary Pheochromocytoma. Horm Cancer. 2012;3:187–192. PubMed PMC

Welsh S, Williams R, Kirkpatrick L, Paine-Murrieta G, Powis G. Antitumor activity and pharmacodynamic properties of PX-478, an inhibitor of hypoxia-inducible factor-1alpha. Mol Cancer Ther. 2004;3:233–244. PubMed

Welsh SJ, Williams RR, Birmingham A, Newman DJ, Kirkpatrick DL, Powis G. The thioredoxin redox inhibitors 1-methylpropyl 2-imidazolyl disulfide and pleurotin inhibit hypoxia-induced factor 1alpha and vascular endothelial growth factor formation. Mol Cancer Ther. 2003;2:235–243. PubMed

Xiao M, Yang H, Xu W, Ma S, Lin H, Zhu H, Liu L, Liu Y, Yang C, Xu Y, et al. 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. 2012;26:1326–1338. PubMed PMC

Xie J, Wang BS, Yu DH, Lu Q, Ma J, Qi H, Fang C, Chen HZ. Dichloroacetate shifts the metabolism from glycolysis to glucose oxidation and exhibits synergistic growth inhibition with cisplatin in HeLa cells. Int J Oncol. 2011;38:409–417. PubMed

Yang C, Matro JC, Huntoon KM, Ye DY, Huynh TT, Fliedner SMJ, Breza J, Zhuang Z, Pacak K. Missense mutations in human SDHB gene increase protein degradation without altering intrinsic enzymatic function. FASEB J. 2012 in press. PubMed PMC

Yankovskaya V, Horsefield R, Tornroth S, Luna-Chavez C, Miyoshi H, Leger C, Byrne B, Cecchini G, Iwata S. Architecture of succinate dehydrogenase and reactive oxygen species generation. Science. 2003;299:700–704. PubMed

Yao L, Schiavi F, Cascon A, Qin Y, Inglada-Perez L, King EE, Toledo RA, Ercolino T, Rapizzi E, Ricketts CJ, et al. Spectrum and prevalence of FP/TMEM127 gene mutations in pheochromocytomas and paragangliomas. JAMA. 2010;304:2611–2619. PubMed

Yeh IT, Lenci RE, Qin Y, Buddavarapu K, Ligon AH, Leteurtre E, Do Cao C, Cardot-Bauters C, Pigny P, Dahia PL. A germline mutation of the KIF1B beta gene on 1p36 in a family with neural and nonneural tumors. Hum Genet. 2008;124:279–285. PubMed

Yu SJ, Yoon JH, Yang JI, Cho EJ, Kwak MS, Jang ES, Lee JH, Kim YJ, Lee HS, Kim CY. Enhancement of hexokinase II inhibitor-induced apoptosis in hepatocellular carcinoma cells via augmenting ER stress and anti-angiogenesis by protein disulfide isomerase inhibition. J Bioenerg Biomembr. 2012;44:101–115. PubMed

Yuneva M. Finding an “Achilles’ heel” of cancer: the role of glucose and glutamine metabolism in the survival of transformed cells. Cell Cycle. 2008;7:2083–2089. PubMed

Zelinka T, Timmers HJ, Kozupa A, Chen CC, Carrasquillo JA, Reynolds JC, Ling A, Eisenhofer G, Lazurova I, Adams KT, et al. Role of positron emission tomography and bone scintigraphy in the evaluation of bone involvement in metastatic pheochromocytoma and paraganglioma: specific implications for succinate dehydrogenase enzyme subunit B gene mutations. Endocr Relat Cancer. 2008;15:311–323. PubMed

Zhang C, Moore LM, Li X, Yung WK, Zhang W. IDH1/2 mutations target a key hallmark of cancer by deregulating cellular metabolism in glioma. Neuro Oncol 2013 PubMed PMC

Zhuang Z, Yang C, Lorenzo F, Merino M, Fojo T, Kebebew E, Popovic V, Stratakis CA, Prchal JT, Pacak K. Somatic HIF2A gain-of-function mutations in paraganglioma with polycythemia. N Engl J Med. 2012;367:922–930. PubMed PMC

Targeting NAD+/PARP DNA Repair Pathway as a Novel Therapeutic Approach to SDHB-Mutated Cluster I Pheochromocytoma and Paraganglioma