TOPK inhibition accelerates oxidative stress‑induced granulosa cell apoptosis via the p53/SIRT1 axis

Abstract

It has been suggested that oxidative stress involving reactive oxygen species (ROS) induces granulosa cell apoptosis, leading to follicular atresia, and that T-lymphokine-activated killer cell-originated protein kinase (TOPK) suppresses cancer cell apoptosis induced by several stimuli. However, it remains to be determined whether TOPK affects oxidative stress-induced granulosa cell apoptosis. The present study demonstrates that TOPK inhibition increases human granulosa cOV434 cell apoptosis induced by hydrogen peroxide (H 2 O 2 ). co-treatment with the TOPK inhibitor, OTS514, in combination with H 2 O 2 increased p53 acetylation and its expression, whereas it decreased Sirtuin 1 (SIRT1) expression, contributing to the promotion of apoptosis. In addition, the SIRT1 activator, resveratrol, or the SIRT1 inhibitor, Ex527, reduced or elevated H 2 O 2 -induced cOV434 cell apoptosis, respectively. Furthermore, the p53 inhibitor, Pifithrin-μ, diminished the augmentation in poly(AdP-ribose) polymerase (PARP) cleavage induced by OTS514 plus H 2 O 2 , while the Mdm2 antagonist, Nutlin 3, increased PARP cleavage. Moreover, OTS514 further decreased the SIRT1 transcriptional activity decreased by H 2 O 2 , but promoted the H 2 O 2 -induced p53 or p21 transcriptional activity. Notably, the expression of exogenous p53 reduced SIRT1 transcriptional activity. Taken together, the findings of the present study demonstrate that TOPK inhibition promotes p53-mediated granulosa cell apoptosis through SIRT1 downregulation in response to H 2 O 2 . Therefore, it can be concluded that TOPK suppresses H 2 O 2 -induced apoptosis through the modulation of the p53/SIRT1 axis, suggesting a potential role of TOPK in the regulation of human granulosa cell apoptosis, leading to the promotion of abnormal follicular development.

Biphasic Effect of TNF-α on the Survival and Endocrine Function of Human Ovarian Granulosa Cells

“…It has been reported that TNF-α inhibits P450 aromatase catalytic activity and inhibin secretion in a dose-dependent manner in granulosa cells [15,[27][28][29]. Our results showed biphasic effects of TNF-α on the expression of P450 aromatase and inhibin and the secretion of E2 and inhibin A in granulosa cells, and the inhibitory effect of the high dose may be attributable to apoptosis, as granulosa cell apoptosis is recognized to play a key role in follicular atresia [30][31][32]. However, other inducible repressors, such as cAMP-responsive element binding modulator (CREM), which participates in the LH-triggered downregulation of aromatase and αinhibin genes [15], probably also contribute to endocrine inhibition, as transcriptional downregulation of P450 aromatase and α-and β-subunits of inhibin were observed in our study.…”

Cordyceps cicadae Ameliorates Renal Hypertensive Injury and Fibrosis Through the Regulation of SIRT1-Mediated Autophagy

“…ROS activates autophagy, which maintains cellular adaptation and reduces oxidative damage by degrading and recycling damaged macromolecules and dysfunctional organelles in cells ( Ornatowski et al, 2020 ). On the other hand, peroxidation levels, such those as of H 2 O 2 and AngII, in abnormal conditions may induce apoptosis via silent information regulator 2 homolog 1 (SIRT1) and other signaling pathways ( Lakhani et al, 2019 ; Park et al, 2020 ; Wu et al, 2020 ; Huang et al, 2021 ). Malondialdehyde (MDA) is a major byproduct in oxidative stress that affects kidney fibrogenesis related to hypertension ( Chen et al, 2019 ).…”

RNA binding protein IGF2BP1 meditates oxidative stress-induced granulosa cell dysfunction by regulating MDM2 mRNA stability in an m6A-dependent manner

“…Additionally, MDM2 also participates in several clinically relevant cellular processes in a p53-independent manner [ 28 , 29 ]. Previous studies have revealed the role of MDM2 in regulating GCs apoptosis, proliferation, follicular development and oocyte quality [ [30] , [31] , [32] ], indicating MDM2 is a key factor in maintaining normal GCs functions and female fertility. The specific mechanisms by which MDM2 is regulated in GCs, however, still remain unclear.…”