Role of the SIRT1/p53 regulatory axis in oxidative stress‑mediated granulosa cell apoptosis

Park,Sang-Ah; Joo,Na-Rae; Park,Jung-Hwan; Oh,Sang-Muk

doi:10.3892/mmr.2020.11658

Role of the SIRT1/p53 regulatory axis in oxidative stress‑mediated granulosa cell apoptosis

Authors:
- Sang-Ah Park
- Na-Rae Joo
- Jung-Hwan Park
- Sang-Muk Oh
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Affiliations: Department of Biochemistry, Priority Research Center, Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon 35365, Republic of Korea
Published online on: November 3, 2020 https://doi.org/10.3892/mmr.2020.11658
Article Number: 20

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Abstract

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 H₂O₂ resulted in human granulosa COV434 cell apoptosis via the regulation of sirtuin 1 (SIRT1)‑mediated p53 activity. Endogenous SIRT1 expression was alleviated by H₂O₂ treatment of COV434 cells in a time‑dependent manner. In addition, knockdown or inhibition of SIRT1 promoted H₂O₂‑induced poly(ADP‑ribose) polymerase (PARP) cleavage and p53 acetylation, which led to an increase in COV434 cell apoptosis. Treatment with H₂O₂ 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 H₂O₂ treatment. Moreover, knockdown of PUMA or PMAIP1 attenuated the H₂O₂ induction of PARP cleavage and COV434 cell apoptosis. In conclusion, the present findings suggested that H₂O₂‑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 H₂O₂‑induced granulosa cell apoptosis.

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