Succinate-to-Fumarate Ratio as a New Metabolic Marker to Detect the Presence of SDHB/D-related Paraganglioma: Initial Experimental and Ex Vivo Findings
Succinate-to-Fumarate Ratio as a New Metabolic Marker to Detect the Presence of SDHB/D-related Paraganglioma: Initial Experimental and Ex Vivo Findings
复制标题
DOI：
10.1210/en.2013-1549
复制
发表时间：
2014-01-01
期刊：
影响因子：
4.8
通讯作者：
Pacak, Karel
中科院分区：
文献类型：
--
作者：
Lendvai, Nikoletta;Pawlosky, Robert;Pacak, Karel
嗜铬细胞瘤（PHEO）和副神经节瘤（PGL;肾上腺外肿瘤）是罕见的神经内分泌嗜铬细胞肿瘤，约30%-35%具有遗传背景。由琥珀酸脱氢酶亚单位B（SDHB）种系突变引起的那些与高转移潜力和最终较高的患者死亡率相关。琥珀酸脱氢酶将琥珀酸转化为富马酸，独特地连接克雷布斯循环和氧化磷酸化。SDH突变导致琥珀酸的积累与各种代谢紊乱和转移到有氧糖酵解在肿瘤组织。在本研究中，我们使用质谱法测量了小鼠嗜铬细胞瘤（MPC）和小鼠肿瘤组织（MTT）细胞以及10例明显散发、10例SDHB-、5例SDHD-和2例神经纤维瘤病1相关PHEO/PGLs和血浆样本中的琥珀酸盐和富马酸盐水平。我们发现SDHB和SDHD相关PGLs的琥珀酸盐/富马酸盐比值显著高于明显散发和神经纤维瘤病1相关PHEO/PGLs（P = 0.0376）。为了进一步支持我们的数据，我们沉默了MPC和MTT细胞中的SDHB表达，并评估了琥珀酸和富马酸水平。与对照样品相比，SDHB沉默的MTT细胞也显示出琥珀酸/富马酸比值的增加（MTT细胞：2.45 vs 7.53），与SDHB相关PGLs的结果相似。本研究结果首次证明了SDHB/D相关PGLs中琥珀酸/富马酸比值显著增加，因此表明该比值可用作检测SDHB/D相关PHEO/PGLs的新代谢标志物。
Pheochromocytomas (PHEOs) and paragangliomas (PGLs; extra-adrenal tumors) are rare neuroendocrine chromaffin cell tumors with a hereditary background in about 30%-35%. Those caused by succinate dehydrogenase subunit B (SDHB) germline mutations are associated with a high metastatic potential and ultimately higher patient mortality. Succinate dehydrogenase converts succinate to fumarate, uniquely linking the Krebs cycle and oxidative phosphorylation. SDH mutations result in the accumulation of succinate associated with various metabolic disturbances and the shift to aerobic glycolysis in tumor tissue. In the present study, we measured succinate and fumarate levels in mouse pheochromocytoma (MPC) and mouse tumor tissue (MTT) cells and in 10 apparently sporadic, 10 SDHB-, 5 SDHD-, and 2 neurofibromatosis 1-related PHEOs/PGLs and plasma samples using mass spectrometry. We found that the succinate-to-fumarate ratio was significantly higher in the SDHB- and SDHD-related PGLs than in apparently sporadic and neurofibromatosis 1-related PHEOs/PGLs (P = .0376). To further support our data, we silenced SDHB expression in MPC and MTT cells and evaluated the succinate and fumarate levels. Compared with control samples, SDHB-silenced MTT cells also showed an increase in the succinate-to-fumarate ratio (MTT cells: 2.45 vs 7.53), similar to the findings in SDHB-related PGLs. The present findings for the first time demonstrate a significantly increased succinate-to-fumarate ratio in SDHB/D-related PGLs and thus suggest this ratio may be used as a new metabolic marker for the detection of SDHB/D-related PHEOs/PGLs.