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Mitotane alters mitochondrial respiratory chain activity by inducing cytochrome coxidase defect in human adrenocortical cells.

Authors :
Ségolène Hescot
Abdelhamid Slama
Anne Lombès
Angelo Paci
Hervé Remy
Sophie Leboulleux
Rita Chadarevian
Séverine Trabado
Larbi Amazit
Jacques Young
Eric Baudin
Marc Lombès
Source :
Endocrine-Related Cancer. Jun2013, Vol. 20 Issue 3, p371-381. 11p.
Publication Year :
2013

Abstract

Mitotane, 1,1-dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl)ethane is the most effective medical therapy for adrenocortical carcinoma, but its molecular mechanism of action remains poorly understood. Although mitotane is known to have mitochondrial (mt) effects, a direct link to mt dysfunction has never been established. We examined the functional consequences of mitotane exposure on proliferation, steroidogenesis, and mt respiratory chain, biogenesis and morphology, in two human adrenocortical cell lines, the steroid-secreting H295R line and the non-secreting SW13 line. Mitotane inhibited cell proliferation in a dose- and a time-dependent manner. At the concentration of 50 μM (14 mg/l), which corresponds to the threshold for therapeutic efficacy, mitotane drastically reduced cortisol and 17-hydroxyprogesterone secretions by 70%. This was accompanied by significant decreases in the expression of genes encoding mt proteins involved in steroidogenesis (STAR, CYP11B1, and CYP11B2). In both H295R and SW13 cells, 50 μM mitotane significantly inhibited (50%) the maximum velocity of the activity of the respiratory chain complex IV (cytochrome coxidase (COX)). This effect was associated with a drastic reduction in steady-state levels of the whole COX complex as revealed by blue native PAGE and reduced mRNA expression of both mtDNA-encoded COX2 (MT-CO2) and nuclear DNA-encoded COX4 (COX4I1) subunits. In contrast, the activity and expression of respiratory chain complexes II and III were unaffected by mitotane treatment. Lastly, mitotane exposure enhanced mt biogenesis (increase in mtDNA content and PGC1α(PPARGC1A) expression) and triggered fragmentation of the mt network. Altogether, our results provide first evidence that mitotane induced a mt respiratory chain defect in human adrenocortical cells. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
13510088
Volume :
20
Issue :
3
Database :
Academic Search Index
Journal :
Endocrine-Related Cancer
Publication Type :
Academic Journal
Accession number :
89426909
Full Text :
https://doi.org/10.1530/ERC-12-0368