Genotype-Specific Abnormalities in Mitochondrial Function Associate with Distinct Profiles of Energy Metabolism and Catecholamine Content in Pheochromocytoma and Paraganglioma

被引：54

作者：

Rao, Jyotsna U. ^{[1
,2
]}

Engelke, Udo F. H. ^{[1
]}

Rodenburg, Richard J. T. ^{[1
,3
]}

Wevers, Ron A. ^{[1
]}

Pacak, Karel ^{[9
]}

Eisenhofer, Graeme ^{[10
,11
]}

Qin, Nan ^{[10
,11
]}

Kusters, Benno ^{[4
,8
]}

Goudswaard, Angelina G. ^{[1
]}

Lenders, Jacques W. M. ^{[5
,10
,11
]}

Hermus, Ad R. M. M. ^{[2
]}

Mensenkamp, Arjen R. ^{[6
]}

Kunst, Henricus P. M. ^{[7
]}

Sweep, Fred C. G. J. ^{[1
]}

Timmers, Henri J. L. M. ^{[2
]}

机构：

[1] Radboud Univ Nijmegen, Med Ctr, Dept Lab Med, Lab Genet Endocrine & Metab Dis, NL-6525 ED Nijmegen, Netherlands

[2] Radboud Univ Nijmegen, Med Ctr, Dept Med, Div Endocrinol, NL-6525 ED Nijmegen, Netherlands

[3] Radboud Univ Nijmegen, Med Ctr, Dept Pediat, NL-6525 ED Nijmegen, Netherlands

[4] Radboud Univ Nijmegen, Med Ctr, Dept Pathol, NL-6525 ED Nijmegen, Netherlands

[5] Radboud Univ Nijmegen, Med Ctr, Dept Med, Div Vasc Med, NL-6525 ED Nijmegen, Netherlands

[6] Radboud Univ Nijmegen, Med Ctr, Dept Genet, NL-6525 ED Nijmegen, Netherlands

[7] Radboud Univ Nijmegen, Med Ctr, Dept Otolaryngol, NL-6525 ED Nijmegen, Netherlands

[8] Maastricht Univ, Med Ctr, Dept Pathol, Maastricht, Netherlands

[9] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA

[10] Univ Hosp Carl Gustav Carus, Dept Med, Dresden, Germany

[11] Univ Hosp Carl Gustav Carus, Inst Clin Chem & Lab Med, Dresden, Germany

来源：

CLINICAL CANCER RESEARCH | 2013年 / 19卷 / 14期

关键词：

ENZYMATIC-ACTIVITY; RESPIRATORY-CHAIN; COMPLEX-II; MUTATIONS; SDHB; TRANSPORTER; EXPRESSION; HYPOXIA; PLASMA; GENE;

D O I：

10.1158/1078-0432.CCR-12-3922

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 1 H-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. (C) 2013 AACR.

引用

页码：3787 / 3795

页数：9

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