Oxidative stress increases the 17,20-lyase-catalyzing activity of adrenal P450c17 through p38α in the development of hyperandrogenism

Publication date: Available online 23 January 2019Source: Molecular and Cellular EndocrinologyAuthor(s): Wenjiao Zhu, Bing Han, Mengxia Fan, Nan Wang, Hao Wang, Hui Zhu, Tong Cheng, Shuangxia Zhao, Huaidong Song, Jie QiaoAbstractUnexplained hyperandrogenic oligoanovulation is a main feature of polycystic ovary syndrome (PCOS). P450c17 phosphorylation selectively increases 17,20-lyase activity and androgen biosynthesis but minimally affects 17α-hydroxylase. Studies have recently identified mitogen-activated protein kinase 14 (MAPK14, p38α) as the kinase responsible for enhancing 17,20-lyase activity through P450c17 phosphorylation. We investigated whether oxidant-induced oxidative stress increases 17,20-lyase activity through oxidant-sensitive p38α signaling pathways. NCI-H295R adrenal cells were treated with three oxidants, palmitate, H2O2 and 4-hydroxy-2-nonenal (HNE), to simulate the excessive oxidative stress of PCOS. Oxidant exposure significantly induced dehydroepiandrosterone production and increased p38α phosphorylation and activation, but the effect on 17α-hydroxyprogesterone production was far less clear. None of the treatments altered the expression of P450c17 or its necessary factors POR and b5. LC-MS/MS revealed increased DHEA production in NCI-H295R cells. Both p38α inhibition and siRNA-mediated silencing attenuated H2O2- or 0.45–0.75 mM PA-mediated augmentation of DHEA production with relatively stable 17OHP levels, indicating that activated p38α medi...
Source: Molecular and Cellular Endocrinology - Category: Endocrinology Source Type: research