The aggressiveness of succinate dehydrogenase subunit B-deficient chromaffin cells is reduced when their bioelectrical properties are restored by glibenclamide.

IF 4.1 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Endocrine-related cancer Pub Date : 2023-08-25 Print Date: 2023-10-01 DOI:10.1530/ERC-23-0167
Francesca Amore, Rachele Garella, Alice Santi, Daniele Guasti, Serena Martinelli, Letizia Canu, Daniele Bani, Jiri Neuzil, Mario Maggi, Roberta Squecco, Elena Rapizzi
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Abstract

Pheochromocytomas/paragangliomas (PPGLs) are neuroendocrine tumours, mostly resulting from mutations in predisposing genes. Mutations of succinate dehydrogenase (SDH) subunit B (SDHB) are associated with high probability of metastatic disease. Since bioelectrical properties and signalling in cancer are an emerging field, we investigated the metabolic, functional and electrophysiological characteristics in human succinate dehydrogenase subunit B (SDHB)-deficient pheochromocytoma cells. These cells exhibited reduced SDH function with elevated succinate-to-fumarate ratio and reduced intracellular ATP levels. The analysis of membrane passive properties revealed a more hyperpolarized membrane potential and a lower cell capacitance of SDHB-deficient cells compared to the parental ones. These bioelectrical changes were associated with reduced proliferation and adhesion capacity of SDHB-deficient cells. Only in SDHB-deficient cells, we also observed an increased amplitude of potassium currents suggesting an activation of ATP-sensitive potassium channels (KATP). Indeed, exposure of the SDHB-deficient cells to glibenclamide, a specific KATP inhibitor, or to ATP caused normalization of potassium current features and altered proliferation and adhesion. In this work, we show for the first time that reduced intracellular ATP levels in SDHB-deficient chromaffin cells impaired cell bioelectrical properties, which, in turn, are associated with an increased cell aggressiveness. Moreover, we first ever demonstrated that glibenclamide not only reduced the outward potassium currents in SDHB-deficient cells but increased their growth capacity, reduced their ability to migrate and shifted their phenotype towards one more similar to that of parental one.

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当格列本脲恢复琥珀酸脱氢酶亚基B缺陷嗜铬细胞的生物电特性时,其攻击性降低。
嗜铬细胞瘤/副神经节瘤(PPGLs)是一种神经内分泌肿瘤,主要由易感基因突变引起。琥珀酸脱氢酶(SDH)亚单位B(SDHB)的突变与转移性疾病的高概率有关。由于癌症的生物电特性和信号传导是一个新兴领域,我们研究了人琥珀酸脱氢酶B亚基(SDHB)缺陷型嗜铬细胞瘤细胞的代谢、功能和电生理特征。这些细胞表现出SDH功能降低,琥珀酸盐与富马酸盐的比例升高,细胞内ATP水平降低。膜被动特性的分析显示,与亲代细胞相比,SDHB缺陷细胞的膜电位更超极化,细胞电容更低。这些生物电变化与SDHB缺陷细胞的增殖和粘附能力降低有关。仅在SDHB缺乏的细胞中,我们还观察到钾电流幅度增加,表明ATP敏感性钾通道(KATP)激活。事实上,SDHB缺陷细胞暴露于特异性KATP抑制剂格列本脲或ATP导致钾电流特征正常化,并改变增殖和粘附。在这项工作中,我们首次表明,SDHB缺陷的嗜铬细胞中细胞内ATP水平的降低损害了细胞的生物电特性,而这反过来又与细胞攻击性的增加有关。此外,我们首次证明,格列本脲不仅减少了SDHB缺陷细胞的外向钾电流,而且增加了它们的生长能力,降低了它们的迁移能力,并使它们的表型向更类似于亲本的表型转变。
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来源期刊
Endocrine-related cancer
Endocrine-related cancer 医学-内分泌学与代谢
CiteScore
7.80
自引率
2.60%
发文量
138
审稿时长
6-12 weeks
期刊介绍: Endocrine-Related Cancer is an official flagship journal of the Society for Endocrinology and is endorsed by the European Society of Endocrinology, the United Kingdom and Ireland Neuroendocrine Society, and the Japanese Hormones and Cancer Society. Endocrine-Related Cancer provides a unique international forum for the publication of high quality original articles describing novel, cutting edge basic laboratory, translational and clinical investigations of human health and disease focusing on endocrine neoplasias and hormone-dependent cancers; and for the publication of authoritative review articles in these topics. Endocrine neoplasias include adrenal cortex, breast, multiple endocrine neoplasia, neuroendocrine tumours, ovary, prostate, paraganglioma, parathyroid, pheochromocytoma pituitary, testes, thyroid and hormone-dependent cancers. Neoplasias affecting metabolism and energy production such as bladder, bone, kidney, lung, and head and neck, are also considered.
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