Open AccessRole of the SIRT1/p53 regulatory axis in oxidative stress‑mediated granulosa cell apoptosis
Author(s) -
SangAh Park,
NaRae Joo,
Jung Hwan Park,
SangMuk Oh
Publication year - 2020
Publication title -
molecular medicine reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.727
H-Index - 56
eISSN - 1791-3004
pISSN - 1791-2997
DOI - 10.3892/mmr.2020.11658
Subject(s) - apoptosis , oxidative stress , gene knockdown , follicular atresia , microbiology and biotechnology , poly adp ribose polymerase , biology , cell cycle , downregulation and upregulation , granulosa cell , chemistry , ovarian follicle , biochemistry , endocrinology , follicular phase , polymerase , gene
Oxidative stress has been suggested to induce granulosa cell apoptosis, which contributes to follicular atresia. However, the mechanism via which oxidative stress mediates granulosa cell apoptosis remains elusive. Therefore, the aim of this study was to elucidate the molecular mechanisms regulating oxidative stress‑induced granulosa cell apoptosis. The present study demonstrated that reactive oxygen species induced by H 2 O 2 resulted in human granulosa COV434 cell apoptosis via the regulation of sirtuin 1 (SIRT1)‑mediated p53 activity. Endogenous SIRT1 expression was alleviated by H 2 O 2 treatment of COV434 cells in a time‑dependent manner. In addition, knockdown or inhibition of SIRT1 promoted H 2 O 2 ‑induced poly(ADP‑ribose) polymerase (PARP) cleavage and p53 acetylation, which led to an increase in COV434 cell apoptosis. Treatment with H 2 O 2 enhanced the expression levels of the p53‑dependent proteins, p53‑upregulated modulator of apoptosis (PUMA) and phorbol‑12‑myristate‑13‑acetate‑induced protein 1 (PMAIP1), as well as those of p53; however, knockdown of p53 decreased cleaved PARP, PUMA and PMAIP1 expression levels induced by H 2 O 2 treatment. Moreover, knockdown of PUMA or PMAIP1 attenuated the H 2 O 2 induction of PARP cleavage and COV434 cell apoptosis. In conclusion, the present findings suggested that H 2 O 2 ‑induced oxidative stress causes granulosa COV434 cell apoptosis via the upregulation of p53 activity by SIRT1 suppression, indicating a mechanistic role of the SIRT1/p53 axis in H 2 O 2 ‑induced granulosa cell apoptosis.