title: Warburg effect's manifestation in aggressive pheochromocytomas and paragangliomas: insights from a mouse cell model applied to human tumor tissue.
abstract: A glycolytic profile unifies a group of pheochromocytomas and paragangliomas (PHEOs/PGLs) with distinct underlying gene defects, including von Hippel-Lindau (VHL) and succinate dehydrogenase B (SDHB) mutations. Nevertheless, their tumor aggressiveness is distinct: PHEOs/PGLs metastasize rarely in VHL-, but frequently in SDHB-patients. To date, the molecular mechanisms causing the more aggressive phenotype in SDHB-PHEOs/PGLs remain largely unknown. Recently, however, an excellent model to study aggressive PHEOs (mouse tumor tissue (MTT) cells) has been developed from mouse PHEO cells (MPC). We employed this model for a proteomics based approach to identify changes characteristic for tumor aggressiveness, which we then explored in a homogeneous set of human SDHB- and VHL-PHEOs/PGLs. The increase of glucose transporter 1 in VHL, and of hexokinase 2 in VHL and SDHB, confirmed their glycolytic profile. In agreement with the cell model and in support of decoupling of glycolysis, the Krebs cycle and oxidative phosphorylation (OXPHOS), SDHB tumors showed increased lactate dehydrogenase levels. In SDHB-PGLs OXPHOS complex activity was increased at complex III and, as expected, decreased at complex II. Moreover, protein and mRNA expression of all tested OXPHOS-related genes were higher in SDHB- than in VHL-derived tumors. Although there was no direct evidence for increased reactive oxygen species production, elevated superoxide dismutase 2 expression may reflect elevated oxidative stress in SDHB-derived PHEOs/PGLs. For the first time, we show that despite dysfunction in complex II and evidence for a glycolytic phenotype, the Warburg effect does not seem to fully apply to SDHB-PHEOs/PGLs with respect to decreased OXPHOS. In addition, we present evidence for increased LDHA and SOD2 expression in SDHB-PHEOs/PGLs, proteins that have been proposed as promising therapeutic targets in other cancers. This study provides new insight into pathogenic mechanisms in aggressive human PHEOs/PGLs, which may lead to identifying new diagnostic and prognostic markers in the near future.
authors.affiliation: Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Stephanie M J
authors.initials: SM
authors.lastname: Fliedner
authors.forename: Nina
authors.initials: N
authors.lastname: Kaludercic
authors.forename: Xiao-Sheng
authors.initials: XS
authors.lastname: Jiang
authors.forename: Hana
authors.initials: H
authors.lastname: Hansikova
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Hajkova
authors.forename: Jana
authors.initials: J
authors.lastname: Sladkova
authors.forename: Andrea
authors.initials: A
authors.lastname: Limpuangthip
authors.forename: Peter S
authors.initials: PS
authors.lastname: Backlund
authors.forename: Robert
authors.initials: R
authors.lastname: Wesley
authors.forename: Lucia
authors.initials: L
authors.lastname: Martiniova
authors.forename: Ivana
authors.initials: I
authors.lastname: Jochmanova
authors.forename: Nikoletta K
authors.initials: NK
authors.lastname: Lendvai
authors.forename: Jan
authors.initials: J
authors.lastname: Breza
authors.forename: Alfred L
authors.initials: AL
authors.lastname: Yergey
authors.forename: Nazareno
authors.initials: N
authors.lastname: Paolocci
authors.forename: Arthur S
authors.initials: AS
authors.lastname: Tischler
authors.forename: Jiri
authors.initials: J
authors.lastname: Zeman
authors.forename: Forbes D
authors.initials: FD
authors.lastname: Porter
authors.forename: Hendrik
authors.initials: H
authors.lastname: Lehnert
authors.forename: Karel
authors.initials: K
authors.lastname: Pacak
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000378:metabolism / Q000473:pathology*; D000313:Adrenal Medulla / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D042967:Electron Transport Complex I / Q000235:genetics / Q000378:metabolism; D042963:Electron Transport Complex II / Q000235:genetics / Q000378:metabolism; D014450:Electron Transport Complex III / Q000235:genetics / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006019:Glycolysis; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption; D010235:Paraganglioma / Q000378:metabolism / Q000473:pathology*; D010673:Pheochromocytoma / Q000378:metabolism / Q000473:pathology*; D020543:Proteome / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D020543:Proteome; D017382:Reactive Oxygen Species; D007770:L-Lactate Dehydrogenase; D042963:Electron Transport Complex II; D003576:Electron Transport Complex IV; D042967:Electron Transport Complex I; D014450:Electron Transport Complex III