Genotype-Specific Abnormalities in Mitochondrial Function Associate with Distinct Profiles of Energy Metabolism and Catecholamine Content in Pheochromocytoma and Paraganglioma
| Autor: | Arjen R. Mensenkamp, Ron A. Wevers, Jyotsna U. Rao, Angelina G. Goudswaard, Henricus P.M. Kunst, Udo F. H. Engelke, Karel Pacak, Graeme Eisenhofer, Nan Qin, Ad Hermus, Jacques W. M. Lenders, Richard J. Rodenburg, Henri J. L. M. Timmers, Benno Kusters, Fred C.G.J. Sweep |
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| Rok vydání: | 2013 |
| Předmět: |
Male
Cancer Research SDHB Adrenal Gland Neoplasms Succinic Acid DCN PAC - Perception action and control Mitochondrion Catecholamines 0302 clinical medicine Paraganglioma Citrate synthase 0303 health sciences Cardiovascular diseases [NCEBP 14] Electron Transport Complex II Succinate dehydrogenase Middle Aged Mitochondria 3. Good health Mitochondrial medicine [IGMD 8] Oncology 030220 oncology & carcinogenesis Female medicine.drug Adult medicine.medical_specialty Adolescent Genotype Pheochromocytoma Biology Article Genomic disorders and inherited multi-system disorders [IGMD 3] Young Adult 03 medical and health sciences Internal medicine ONCOL 3 - Translational research DCN MP - Plasticity and memory medicine Humans Glycostation disorders [DCN PAC - Perception action and control IGMD 4] DCN NN - Brain networks and neuronal communication 030304 developmental biology Translational research Genomic disorders and inherited multi-system disorders [ONCOL 3] Hormonal regulation [IGMD 6] Glycostation disorders [IGMD 4] medicine.disease Endocrinology Hereditary cancer and cancer-related syndromes Genomic disorders and inherited multi-system disorders [ONCOL 1] biology.protein Catecholamine Hormonal regulation Aetiology screening and detection [IGMD 6] SDHD Energy Metabolism |
| Zdroj: | Clinical Cancer Research; Vol 19 Clinical Cancer Research, 19, 3787-95 Clinical Cancer Research, 19, 14, pp. 3787-95 |
| ISSN: | 1557-3265 1078-0432 |
| Popis: | Purpose: Pheochromocytomas and paragangliomas (PGL) are neuroendocrine tumors of sympathetic and parasympathetic paraganglia. This study investigated the relationships between genotype-specific differences in mitochondrial function and catecholamine content in PGL tumors. Experimental Design: Respiratory chain enzyme assays and 1H-nuclear magnetic resonance (NMR) spectroscopy at 500 MHz were conducted on homogenates of 35 sporadic PGLs and 59 PGLs from patients with hereditary mutations in succinate dehydrogenase subunits B and D (SDHB, SDHD), succinate dehydrogenase assembly factor 2, von Hippel-Lindau (VHL), rearranged during transfection (RET), neurofibromatosis type 1 (NF1), and myc-associated factor X. Results: In SDHx-related PGLs, a significant decrease in complex II activity (P < 0.0001) and a significant increase in complex I, III, and IV enzyme activities were observed when compared to sporadic, RET, and NF1 tumors. Also, a significant increase in citrate synthase (P < 0.0001) enzyme activity was observed in SDHx-related PGLs when compared to sporadic-, VHL-, RET-, and NF1-related tumors. An increase in succinate accumulation (P < 0.001) and decrease in ATP/ADP/AMP accumulation (P < 0.001) was observed when compared to sporadic PGLs and PGLs of other genotypes. Positive correlations (P < 0.01) were observed between respiratory chain complex II activity and total catecholamine content and ATP/ADP/AMP and total catecholamine contents in tumor tissues. Conclusions: This study for the first time establishes a relationship between determinants of energy metabolism, like activity of respiratory chain enzyme complex II, ATP/ADP/AMP content, and catecholamine content in PGL tumors. Also, this study for the first time successfully uses NMR spectroscopy to detect catecholamines in PGL tumors and provides ex vivo evidence for the accumulation of succinate in PGL tumors with an SDHx mutation. Clin Cancer Res; 19(14); 3787–95. ©2013 AACR. |
| Databáze: | OpenAIRE |
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