Vanin-1 Inactivation Antagonizes the Development of Adrenocortical Neoplasia in Sf-1 Transgenic Mice

• Published in: Endocrinology (Philadelphia) 2014-07, Vol.155 (7), p.2349-2354
• Main Authors: Latre de Late, Perle, El Wakil, Abeer, Jarjat, Marielle, de Krijger, Ronald R, Heckert, Leslie L, Naquet, Philippe, Lalli, Enzo
• Format: Article
• Language: English
• Subjects: Ablation; Adrenal cortex; Adrenal Cortex - drug effects; Adrenal Cortex - metabolism; Adrenal Cortex - pathology; Adrenal Cortex Neoplasms - genetics; Adrenal Cortex Neoplasms - metabolism; Amidohydrolases - genetics; Amidohydrolases - metabolism; Animals; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cysteamine; Cysteamine - metabolism; Cysteamine - pharmacology; Detoxification; Disease Progression; Female; Glutathione; Glutathione - metabolism; GPI-Linked Proteins - genetics; GPI-Linked Proteins - metabolism; Hyperplasia; Immunohistochemistry; Inactivation; Lesions; Male; Mice; Mice, Knockout; Mice, Transgenic; Models, Biological; Oxidative stress; Pathogenesis; Reactive Oxygen Species - metabolism; Steroidogenic Factor 1 - genetics; Steroidogenic Factor 1 - metabolism; Time Factors; Transgenic animals; Transgenic mice
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2014-1088

SF-1 (NR5A1) overexpression can induce adrenocortical tumor formation in transgenic mice and is associated with more severe prognosis in patients with adrenocortical cancer. In this study we have identified Vanin-1 (Vnn1), a SF-1 target gene, as a novel modulator of the tumorigenic effect of Sf-1 overexpression in the adrenal cortex. Vanin-1 is endowed with pantetheinase activity, releasing cysteamine in tissues and regulating cell response to oxidative stress by modulating the production of glutathione. Sf-1 transgenic mice developed adrenocortical neoplastic lesions (both dysplastic and nodular) with a frequency increasing with age. Genetic ablation of the Vnn1 gene in Sf-1 transgenic mice significantly reduced the severity of neoplastic lesions in the adrenal cortex. This effect could be reversed by treatment of Sf-1 transgenic/Vnn1 null mice with cysteamine. These data show that alteration of the mechanisms controlling intracellular redox and detoxification mechanisms is relevant to the pathogenesis of adrenocortical neoplasia induced by SF-1 overexpression.