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

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 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.

NAD+ in Alzheimer’s Disease: Molecular Mechanisms and Systematic Therapeutic Evidence Obtained in vivo

“…As a transcription factor, p53 induces apoptosis and is inhibited by SIRT1 deacetylation at several cellular locations, and SIRT1-deficient cells possess hyperacetylated p53 ( Luna et al, 2013 ). In contrast, p53 can inhibit SIRT1 expression when nutrients are abundant through p53-binding sites on the SIRT1 promoter ( Park et al, 2021 ). In the past decade, emerging evidence has indicated that the function of p53 is directly modulated by PARP-1 ( Elkholi and Chipuk, 2014 ).…”

Epigenetics of Sirtuins: Relevance to Hepatocellular Carcinoma

“…Notably, the activation of AMPK reduces a variety of cancer symptoms, including HCC [87]. Recent studies have shown that AMPK directly phosphorylates SIRT1 at Thr344 to reduce SIRT1 deacetylase activity on p53 and then inhibits the development of cancer by activating the p53-dependent apoptosis pathway [88]. These results demonstrate that the AMPK signaling pathway inhibits the occurrence and migration of HCC [89].…”

Regulation of SIRT1 in Ovarian Function: PCOS Treatment

“…A subsequent study by the authors revealed the existence of a feedback mechanism between FOXL2 and SIRT1: FOXL2 activates SIRT1 transcription and upregulates its expression through promoter binding, while SIRT1 plays a regulatory role by deacetylating FOXL2, thus maintaining the homeostasis of the ovarian follicle internal environment. A subsequent study by Park et al also found that H 2 O 2 induced oxidative stress by inhibiting the SIRT1 upregulation of p53 activity, which led to granulosa cell apoptosis, thus suggesting a mechanistic role of the SIRT1/p53 axis in H 2 O 2 -induced granulosa cell apoptosis [ 27 ]. Ding et al showed that the combined effect of hepatocyte growth factor (HGF) and basic fibroblast growth factor (BFGF), secreted by human adipose stem cells, slowed the natural aging process by activating the SIRT1/FOXO1 signaling pathway, reducing ROS production and oxidative stress [ 28 ].…”