Current views on cell metabolism in SDHx-related pheochromocytoma and paraganglioma.
Current views on cell metabolism in SDHx-related pheochromocytoma and paraganglioma.
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DOI：
10.1530/erc-13-0398
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发表时间：
2014-06
影响因子：
3.9
通讯作者：
Pacak K
中科院分区：
文献类型：
--
作者：
Vicha A;Taieb D;Pacak K
瓦尔堡的代谢假说基于这样的假设：癌细胞的呼吸必须受到攻击，导致其损伤，以获得增加的糖酵解。尽管这可能不适用于所有癌症，但有一些证据证明主要功能异常的线粒体复合物确实与癌症的发展有关。因此，复合体 II（琥珀酸脱氢酶（SDH））的突变导致嗜铬细胞瘤/副神经节瘤的形成。 SDH 基因之一的突变（SDHx 突变）会导致琥珀酸积累，并与极低的富马酸水平、谷氨酰胺分解增加、活性氧 (ROS) 的产生和假性缺氧相关。这导致信号通路发生显着变化（其中许多依赖于缺氧诱导因子（HIF）的稳定），包括氧化磷酸化、糖酵解、特异性表达谱，以及导致肿瘤发展的基因组不稳定性和突变性增加。尽管目前对于 SDHx 相关的转移性嗜铬细胞瘤/副神经节瘤还没有非常有效的治疗方法，但针对其基本代谢异常可能为开发针对这些肿瘤的新颖且更有效的治疗形式提供独特的机会。
Warburg’s metabolic hypothesis is based on the assumption that a cancer cell’s respiration must be under attack, leading to its damage, in order to obtain increased glycolysis. Although this may not apply to all cancers, there is some evidence proving that primarily abnormally functioning mitochondrial complexes are indeed related to cancer development. Thus, mutations in complex II (succinate dehydrogenase (SDH)) lead to the formation of pheochromocytoma/paraganglioma. Mutations in one of the SDH genes (SDHx mutations) lead to succinate accumulation associated with very low fumarate levels, increased glutaminolysis, the generation of reactive oxygen species (ROS), and pseudohypoxia. This results in significant changes in signaling pathways (many of them dependent on the stabilization of hypoxia-inducible factor (HIF)) including oxidative phosphorylation, glycolysis, specific expression profiles, as well as genomic instability and increased mutability resulting in tumor development. Although there is currently no very effective therapy for SDHx-related metastatic pheochromocytomas/paragangliomas, targeting their fundamental metabolic abnormalities may provide a unique opportunity for the development of novel and more effective forms of therapy for these tumors.