Current views on cell metabolism in SDHx-related pheochromocytoma and paraganglioma

Vícha, Aleš; Taïeb, David; Pacák, Karel

doi:10.1530/erc-13-0398

Cited by 30 publications

(48 citation statements)

References 210 publications

(280 reference statements)

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“…SDH dysfunction, arising as a result of mutations within any of the four SDH subunits, has been correlated with a range of diseases, including hereditary PC and PGL syndromes, renal cell carcinoma, gastrointestinal stromal tumours and Leigh syndrome (Horvath et al 2006, Vicha et al 2014. In general, PC and PGL tumours containing germline SDH gene mutations exhibit markedly diminished SDH function (Gimenez-Roqueplo et al 2002).…”

Section: Discussionmentioning

confidence: 99%

Structural and functional consequences of succinate dehydrogenase subunit B mutations

Kim¹,

Rath²,

Tsang³

et al. 2015

Endocrine-Related Cancer

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Mitochondrial dysfunction, due to mutations of the gene encoding succinate dehydrogenase (SDH), has been implicated in the development of adrenal phaeochromocytomas, sympathetic and parasympathetic paragangliomas, renal cell carcinomas, gastrointestinal stromal tumours and more recently pituitary tumours. Underlying mechanisms behind germline SDH subunit B (SDHB) mutations and their associated risk of disease are not clear. To investigate genotype-phenotype correlation of SDH subunit B (SDHB) variants, a homology model for human SDH was developed from a crystallographic structure. SDHB mutations were mapped, and biochemical effects of these mutations were predicted in silico. Results of structural modelling indicated that many mutations within SDHB are predicted to cause either failure of functional SDHB expression (p.Arg27*, p.Arg90*, c.88delC and c.311delAinsGG), or disruption of the electron path (p.Cys101Tyr, p.Pro197Arg and p.Arg242His). GFP-tagged WT SDHB and mutant SDHB constructs were transfected (HEK293) to determine biological outcomes of these mutants in vitro. According to in silico predictions, specific SDHB mutations resulted in impaired mitochondrial localisation and/or SDH enzymatic activity. These results indicated strong genotype-functional correlation for SDHB variants. This study reveals new insights into the effects of SDHB mutations and the power of structural modelling in predicting biological consequences. We predict that our functional assessment of SDHB mutations will serve to better define specific consequences for SDH activity as well as to provide a much needed assay to distinguish pathogenic mutations from benign variants.

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Section: Discussionmentioning

confidence: 99%

Structural and functional consequences of succinate dehydrogenase subunit B mutations

Kim¹,

Rath²,

Tsang³

et al. 2015

Endocrine-Related Cancer

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“…Current data suggests that most of the PHEO/PGL susceptibility gene mutations are associated with dysregulation of several metabolic pathways, which subsequently leads to defects in hypoxia signaling pathways and adaptive responses (18, 56). Pseudohypoxia and mitochondrial enzymes disruption may have a direct oncogenic or tumor suppressive effect by regulating and controlling diverse cellular processes (57–59).…”

Section: Metabolic Alterations In Pheos/pglsmentioning

confidence: 99%

Pheochromocytoma: The First Metabolic Endocrine Cancer

Jochmanová

Pacák

2016

Clinical Cancer Research

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Dysregulated metabolism is one of the key characteristics of cancer cells. The most prominent alterations are present during regulation of cell respiration, which leads to a switch from oxidative phosphorylation to aerobic glycolysis. This metabolic shift results in activation of numerous signaling and metabolic pathways supporting cell proliferation and survival. Recent progress in genetics and metabolomics allowed us to take a closer look at the metabolic changes present in pheochromocytomas and paragangliomas (PHEOs/PGLs). These neuroendocrine tumors often exhibit dysregulation of mitochondrial metabolism, which is driven by mutations in genes encoding Krebs cycle enzymes or by activation of hypoxia signaling. Present metabolic changes are involved in processes associated with tumorigenesis, invasiveness, metastasis, and resistance to various cancer therapies. In this review, we discuss the metabolic nature of PHEOs/PGLs and how unveiling the metabolic disturbances present in tumors could lead to identification of new biomarkers and personalized cancer therapies.

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“…Cluster 1 contains tumors (mostly extraadrenal) with mutations in the von Hippel-Lindau tumor suppressor (VHL), components of the succinate dehydrogenase complex (subunits A-D and its flavination factor SDHAF2), hypoxia-inducible factor 2-alpha, also called EPAS1 (HIF2A), fumarate hydratase (FH), prolyl hydroxylase domain-containing protein 1 (PHD1), and PHD2 genes that are associated with a pseudohypoxic signature and the activation of mainly the HIF-2alpha signaling pathway (Jochmanova et al 2013). These tumors can be separated by their transcription profile from neoplasms (mostly PHEOs) with mutations in Ret Proto-Oncogene (RET), neurofibromin 1 (NF1), transmembrane protein 127 (TMEM127), and MYC associated factor X (MAX) mutations, which are associated with increased kinase signaling as well as Printed in Great Britain combined HIF-1alpha and HIF-2alpha signaling pathways (Jochmanova et al 2013, Vicha et al 2014. PHEOs/PGLs provide unique opportunities for discovering and proving a genotype-related imaging phenotype.…”

Section: Influence Of Genotype On Imaging Phenotypementioning

confidence: 99%

15 YEARS OF PARAGANGLIOMA: Imaging and imaging-based treatment of pheochromocytoma and paraganglioma

Castinetti¹,

Kroiss²,

Kumar³

et al. 2015

Endocrine-Related Cancer

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Although anatomic imaging to assess the precise localization of pheochromocytomas/ paragangliomas (PHEOs/PGLs) is unavoidable before any surgical intervention on these tumors, functional imaging is becoming an inseparable portion of the imaging algorithm for these tumors. This review article presents applications of the most up-to-date functional imaging modalities and image-based treatment to PHEOs/PGLs patients. Functional imaging techniques provide whole-body localization (number of tumors present along with metastatic deposits) together with genetic-specific imaging approaches to PHEOs/PGLs, thus enabling highly specific and sensitive PHEO/PGL detection and delineation that now greatly impact the management of patients. Radionuclide imaging techniques also play a crucial role in the prediction of possible radioactive treatment options for PHEO/PGL. In contrast to previous imaging algorithms used for either assessement of these patients or their follow-up, endocrinologists, surgeons, oncologists, pediatricians, and other specialists require functional imaging before any therapeutic plan is outlined to the patient, and follow-up, especially in patients with metastatic disease, is based on the periodic use of functional imaging, often reducing or substituting for anatomical imaging. In similar specific indications, this will be further powered by using PET/MR in the assessment of these tumors. In the near future, it is expected that PHEO/PGL patients will benefit even more from an assessement of the functional characteristics of these tumors and new imaging-based treatment options. Finally, due to the use of new targeting moieties, gene-targeted radiotherapeutics and nanobodiesbased theranostic approaches are expected to become a reality in the near future.

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Current views on cell metabolism in SDHx-related pheochromocytoma and paraganglioma

Cited by 30 publications

References 210 publications

Structural and functional consequences of succinate dehydrogenase subunit B mutations

Structural and functional consequences of succinate dehydrogenase subunit B mutations

Pheochromocytoma: The First Metabolic Endocrine Cancer

15 YEARS OF PARAGANGLIOMA: Imaging and imaging-based treatment of pheochromocytoma and paraganglioma

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