Oxidative stress increases the 17, 20-lyase-catalyzing activity of adrenal P450c17 through p38α in the development of hyperandrogenism. (15th March 2019)

• Record Type: Journal Article
• Authors: Zhu, Wenjiao; Han, Bing; Fan, Mengxia; Wang, Nan; Wang, Hao; Zhu, Hui; Cheng, Tong; Zhao, Shuangxia; Song, Huaidong; Qiao, Jie
• Is Part Of: Molecular and cellular endocrinology. Volume 484(2019)
• Page Start: 25
• Page End: 33
• Publication Date: 2019-03-15
• Subjects: Oxidative stress -- P450c17 -- p38α mitogen-activated protein kinase -- Androgen; Endocrinology -- Periodicals; Molecular biology -- Periodicals; Cytology -- Periodicals; Endocrinology -- Periodicals; Hormones -- Periodicals; Endocrinologie -- Périodiques; Cytology; Endocrinology; Molecular biology; Periodicals; 573.4
• DOI: 10.1016/j.mce.2019.01.020
• Languages: English
• ISSNs: 0303-7207

Abstract

Abstract: Unexplained 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, H2 O2 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 H2 O2 - or 0.45–0.75 mM PA-mediated augmentation of DHEA production with relatively stable 17OHP levels, indicating that activated p38α mediates oxidative stress-induced 17, 20-lyase activation and androgen synthesis stimulation, which may underlie hyperandrogenism in PCOS. Highlights: Phosphorylation of p38α mediates oxidative stress-induced 17, 20-lyase activity. Differential regulation of P450c17 may contribute to the mechanism of hyperandrogenism in PCOS. p38α pathway may be a nexus between insulin resistance and hyperandrogenism that is triggered by oxidative stress.