IJC International Journal of Cancer
Oncometabolites-driven tumorigenesis: From genetics to targeted therapy 1
INSERM, UMR970, Paris-Cardiovascular Research Center at HEGP, Paris, France Faculte de Medecine, Universite Paris Descartes, Paris, France 3 Programme Cartes d’Identit e des Tumeurs, Ligue Nationale Contre Le Cancer, Paris, France 4 ^pitaux de Paris, Ho ^pital Europeen Georges Pompidou, Service de G Assistance Publique-Ho en etique, Paris, France 2
Although the alteration of cellular metabolism in cancer was reported by Warburg in the early 1930s, a regain of interest in cancer metabolism has more recently followed the discovery of germline or somatic mutations in genes coding for metabolic enzymes (succinate dehydrogenase, fumarate hydratase and isocitrate dehydrogenase) that are associated with tumor susceptibility. Mutations in these genes are found in numerous tumor types including paragangliomas, kidney cancers, leiomyomas, glioblastomas and acute myeloid leukemia. They lead to the accumulation of so-called oncometabolites that behave as competitors of 2-oxoglutarate-dependent dioxygenases, involved in a broad spectrum of pathways such as hypoxic response and epigenetic reprogramming. Here, we review the diverse pathways affected by oncometabolites, their potential role in cancer formation, maintenance, metastasis and sensitivity to chemotherapies, as well as emerging new therapeutic strategies.
Metabolic reprogramming is emerging as a core hallmark of cancer.1 Over the last 15 years, considerable evidence has been accumulated to show that most oncogenes and tumor suppressors regulate cell metabolism; therefore, mutations in these genes promote the deregulated use of nutrients that facilitate cell survival and proliferation. Altered metabolism has been linked to tumorigenesis and resistance to cancer therapies. This has led to the reemergence of interest in the concept of aerobic glycolysis or "Warburg effect" reported by Otto Warburg in the early 1930s, which is characterized by high glucose consumption and lactate production, even in the presence of oxygen.2 These general metabolic alterations and therapeutics that target them have been largely reviewed
Key words: metabolism, oncometabolite, paraganglioma, pheochromocytoma, glioblastoma, SDH, FH, IDH, hypoxia, epigenetics Grant sponsor: Agence Nationale de la Recherche; Grant number: ANR-2011-JCJC-00701 MODEOMAPP; Grant sponsor: European Union Seventh Framework Programme FP7/2007-2013; Grant number: 259735; Grant sponsor: Programme Hospitalier de Recherche Clinique; Grant number: COMETE 3 AOM 06 179; enetique et Cancer Grant sponsor: Plan Cancer Action (AAP Epig 2013, U970-C13089KS-INSERM PLAN CANCER); Grant number: 3.2 2009-2013 DOI: 10.1002/ijc.29080 History: Received 6 Feb 2014; Accepted 16 Apr 2014; Online 14 Aug 2014 Correspondence to: Dr. Judith Favier, INSERM UMR970, Centre de Recherche Cardiovasculaire de l’HEGP, 56 rue Leblanc, 75015 Paris, France, Tel.: 133-1-53-98-80-41, Fax: 133-1-53-98-79-52, E-mail:
[email protected] C 2014 UICC Int. J. Cancer: 135, 2237–2248 (2014) V
elsewhere.1,3,4 Recent evidence has shown that mitochondrial enzyme genes may have direct oncogenic or tumor suppressive properties by controlling various cellular processes. Here, we will focus on cancer-associated mutations in mitochondrial enzymes and their recently discovered consequences. In the early 2000s, the discovery of a germline mutation in the SDHD gene in a family suffering from hereditary paraganglioma (PGL) demonstrated that a mitochondrial enzyme may have a tumor suppressor function.5 PGL are rare, usually benign, neuroendocrine tumors that occur in paraganglia. They develop in the parasympathetic nervous system (glomus tympanic and glomus jugular in the head, the carotid body and glomus vagus in the neck) or in the sympathetic extra-adrenal nervous system (thoraco-abdominal-pelvic sympathetic ganglia). If the tumor occurs in the adrenal medulla, it is called a pheochromocytoma (PCC). The SDHD gene encodes one of the four subunits of succinate dehydrogenase (SDH), a mitochondrial enzyme that catalyzes the oxidation of succinate to fumarate in the Krebs cycle and transfers electrons to the ubiquinone pool in the respiratory chain. We6 and others7,8 have identified constitutional mutations in the genes encoding the other SDH subunits (SDHA, B and C) as well as mutations in the SDH assembly factor (SDHAF2)9 in inherited or apparently sporadic forms of PGL/PCC. SDHA and SDHB mutations are also found in patients with gastrointestinal stromal tumors (GIST)10,11 and in kidney cancer (RCC).12 SDH was thus the first mitochondrial enzyme to be implicated in predisposition to a hereditary cancer. This finding was unexpected because it was previously thought that mitochondrial defects were only responsible for neurodegenerative diseases such as Leigh syndrome (SDHA mutations) or encephalopathies of various severities and time of onset [mutations in genes encoding
Special Section Paper
lie Morin1,2, Eric Letouze 3, Anne-Paule Gimenez-Roqueplo1,2,4 and Judith Favier1,2 Aure
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Oncometabolites-driven tumorigenesis
Table 1. Summary of metabolic genes involved in cancer and the associated tumor types
Special Section Paper
Gene SDHA, SDHB, SDHC, SDHD, SDHAF2
Enzyme
Tumor types (frequency of mutations)
Succinate dehydrogenase (SDH)
Pheochromocytoma/paraganglioma (20%), GIST (