Oxidative stress increases the 17,20-lyase-catalyzing activity of adrenal P450c17 through p38α in the development of hyperandrogenism.
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, 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 mediates oxidative stress-induced 17,20-lyase activation and androgen synthesis stimulation, which may underlie hyperandrogenism in PCOS.
['Zhu|Wenjiao|W|', 'Han|Bing|B|', 'Fan|Mengxia|M|', 'Wang|Nan|N|', 'Wang|Hao|H|', 'Zhu|Hui|H|', 'Cheng|Tong|T|', 'Zhao|Shuangxia|S|', 'Song|Huaidong|H|', 'Qiao|Jie|J|']
D000447:Aldehydes D002460:Cell Line D003687:Dehydroepiandrosterone D004789:Enzyme Activation D006801:Humans D006861:Hydrogen Peroxide D017588:Hyperandrogenism D048308:Mitogen-Activated Protein Kinase 14 D018384:Oxidative Stress D019308:Palmitic Acid D010766:Phosphorylation D017382:Reactive Oxygen Species D013254:Steroid 17-alpha-Hydroxylase D015854:Up-Regulation
Oxidative stress P450c17 Androgen p38α mitogen-activated protein kinase