Research Paper|Volume 13, Issue 3|pp 4617—4633

LNK promotes granulosa cell apoptosis in PCOS via negatively regulating insulin-stimulated AKT-FOXO3 pathway

Min Tan¹, Yanxiang Cheng², Xiaozhu Zhong¹, Dongyong Yang², Sushi Jiang¹, Yang Ye¹, Miao Ding¹, Guijun Guan³, Dongzi Yang¹, Xiaomiao Zhao¹

¹Department of Obstetrics and Gynecology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
²Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei, China
³Shanghai Collaborative Innovation for Aquatic Animal Genetics and Breeding, College of Fisheries and Life Sciences, Shanghai Ocean University, Shanghai 201306, China

* Co-first authors

Received: October 3, 2020Accepted: November 17, 2020Published: January 20, 2021

https://doi.org/10.18632/aging.202421

Copyright: © 2021 Tan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Background: Polycystic ovary syndrome (PCOS), which is often accompanied by insulin resistance, is closely related to increased apoptosis of ovarian granulosa cells. LNK is an important regulator of the insulin signaling pathway. When insulin binds to the receptor, the PI3K/AKT/FOXO signaling pathway is activated, and FOXO translocates from the nucleus to the cytoplasm, thereby inhibiting the expression of pro-apoptotic genes.

Methods: Granulosa cells were collected from PCOS patients to investigate the relationship between LNK, cell apoptosis and insulin resistance. KGN cells underwent LNK overexpression/silence and insulin stimulation. The AKT/FOXO3 pathway was studied by western blot and immunofluorescence. LNK knockout mice were used to investigate the effect of LNK on the pathogenesis of PCOS.

Results: The level of LNK was higher in PCOS group than control group. LNK was positively correlated with granulosa cell apoptosis and insulin resistance, and negatively correlated with oocyte maturation rate. LNK overexpression in KGN cells inhibited insulin-induced AKT/FOXO3 signaling pathway, causing nucleus translocation of FOXO3 and promoting granulosa cell apoptosis. LNK knockout partially restored estrous cycle and improved glucose metabolism in PCOS mice.

Conclusions: LNK was closely related to insulin resistance and apoptosis of granulosa cells via the AKT/FOXO3 pathway. LNK knockout partially restored estrous cycle and improved glucose metabolism in PCOS mice, suggesting LNK might become a potential biological target for the clinical treatment of PCOS.