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

in Endocrine-Related Cancer
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Francesca Amore Department Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy

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Rachele Garella Department Experimental and Clinical Medicine, University of Florence, Florence, Italy

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Alice Santi Department Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy

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Daniele Guasti Department of Experimental and Clinical Medicine, Imaging Platform, University of Florence, Italy

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Serena Martinelli Department Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
Centro di Ricerca e Innovazione sulle Patologie Surrenaliche, AOU Careggi, Florence, Italy
ENS@T Center of Excellence, Florence, Italy

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Letizia Canu Department Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
Centro di Ricerca e Innovazione sulle Patologie Surrenaliche, AOU Careggi, Florence, Italy
ENS@T Center of Excellence, Florence, Italy

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Daniele Bani Department of Experimental and Clinical Medicine, Imaging Platform, University of Florence, Italy

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Jiri Neuzil Institute of Biotechnology, Czech Academy of Sciences, Prague-West, Czech Republic
School of Pharmacy and Medical Science, Griffith University, Southport, Queensland, Australia
Faculty of Science and 1st Medical Faculty, Charles University, Prague, Czech Republic

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Mario Maggi Department Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
Centro di Ricerca e Innovazione sulle Patologie Surrenaliche, AOU Careggi, Florence, Italy
ENS@T Center of Excellence, Florence, Italy

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Roberta Squecco Department Experimental and Clinical Medicine, University of Florence, Florence, Italy

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Elena Rapizzi Department Experimental and Clinical Medicine, University of Florence, Florence, Italy
Centro di Ricerca e Innovazione sulle Patologie Surrenaliche, AOU Careggi, Florence, Italy
ENS@T Center of Excellence, Florence, Italy

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https://orcid.org/0000-0002-3826-2714

Correspondence should be addressed to E Rapizzi: elena.rapizzi@unifi.it

*(F Amore and R Garella contributed equally to this work)

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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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