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

0583191 - BTÚ 2024 RIV GB eng J - Journal Article
Amore, F. - Garella, R. - Santi, A. - Guasti, D. - Martinelli, S. - Canu, L. - Bani, D. - Neužil, Jiří - Maggi, M. - Squecco, R. - Rapizzi, E.
The aggressiveness of succinate dehydrogenase subunit B-deficient chromaffin cells is reduced when their bioelectrical properties are restored by glibenclamide.
Endocrine-Related Cancer. Roč. 30, č. 10 (2023), č. článku e230167. ISSN 1351-0088. E-ISSN 1479-6821
R&D Projects: GA ČR(CZ) GX21-04607X
Institutional support: RVO:86652036
Keywords : sensitive potassium channels * k-atp channels * ion channels * growth-factor * complex-ii * microenvironment
OECD category: Endocrinology and metabolism (including diabetes, hormones)
Impact factor: 3.9, year: 2022
Method of publishing: Limited access
https://erc.bioscientifica.com/view/journals/erc/30/10/ERC-23-0167.xml

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 (K-ATP). Indeed, exposure of the SDHB-deficient cells to glibenclamide, a specific K-ATP 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.
Permanent Link: https://hdl.handle.net/11104/0351196