TOPK inhibition accelerates oxidative stressinduced granulosa cell apoptosis via the p53/SIRT1 axis.
Int J Mol Med
; 46(5): 1923-1937, 2020 Nov.
Article
en En
| MEDLINE
| ID: mdl-32901866
ABSTRACT
It has been suggested that oxidative stress involving reactive oxygen species (ROS) induces granulosa cell apoptosis, leading to follicular atresia, and that Tlymphokineactivated killer celloriginated protein kinase (TOPK) suppresses cancer cell apoptosis induced by several stimuli. However, it remains to be determined whether TOPK affects oxidative stressinduced granulosa cell apoptosis. The present study demonstrates that TOPK inhibition increases human granulosa COV434 cell apoptosis induced by hydrogen peroxide (H2O2). Cotreatment with the TOPK inhibitor, OTS514, in combination with H2O2 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 H2O2induced COV434 cell apoptosis, respectively. Furthermore, the p53 inhibitor, Pifithrinµ, diminished the augmentation in poly(ADPribose) polymerase (PARP) cleavage induced by OTS514 plus H2O2, while the Mdm2 antagonist, Nutlin 3, increased PARP cleavage. Moreover, OTS514 further decreased the SIRT1 transcriptional activity decreased by H2O2, but promoted the H2O2induced 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 p53mediated granulosa cell apoptosis through SIRT1 downregulation in response to H2O2. Therefore, it can be concluded that TOPK suppresses H2O2induced 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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Proteína p53 Supresora de Tumor
/
Apoptosis
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Estrés Oxidativo
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Quinasas de Proteína Quinasa Activadas por Mitógenos
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Sirtuina 1
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Células de la Granulosa
Límite:
Female
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Humans
Idioma:
En
Revista:
Int J Mol Med
Asunto de la revista:
BIOLOGIA MOLECULAR
/
GENETICA MEDICA
Año:
2020
Tipo del documento:
Article