Cyproterone Acetate Mediates IRE1α Signaling Pathway to Alleviate Pyroptosis of Ovarian Granulosa Cells Induced by Hyperandrogen
Objective: Hyperandrogenemia (HA) is the main pathophysiological change that takes place in polycystic ovary syndrome (PCOS). Cyproterone acetate (CYA) is a drug commonly used to reduce androgen in patients with PCOS. Long-term and continuous exposure to HA can cause ovarian granulosa cells (GCs), p...
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MDPI AG
2022-12-01
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| author | Yan Zhang Xianguo Xie Yabo Ma Changzheng Du Yuan Jiao Guoliang Xia Jinrui Xu Yi Yang |
| author_facet | Yan Zhang Xianguo Xie Yabo Ma Changzheng Du Yuan Jiao Guoliang Xia Jinrui Xu Yi Yang |
| author_sort | Yan Zhang |
| collection | DOAJ |
| description | Objective: Hyperandrogenemia (HA) is the main pathophysiological change that takes place in polycystic ovary syndrome (PCOS). Cyproterone acetate (CYA) is a drug commonly used to reduce androgen in patients with PCOS. Long-term and continuous exposure to HA can cause ovarian granulosa cells (GCs), pyroptotic death, and follicular dysfunction in PCOS mice. The aim of this study was to investigate whether CYA could ameliorate the hyperandrogenemia-induced pyroptosis of PCOS ovarian GCs by alleviating the activation of the IRE1α signaling pathway. Methods: Firstly, thirty PCOS patients with HA as their main clinical manifestation were selected as the study group, and thirty non-PCOS patients were selected as the control group. The GCs and follicular fluid of the patients were collected, and the expression of pyroptosis-related proteins was detected. Secondly, a PCOS mouse model induced by dehydroepiandrosterone (DHEA) was constructed, and the treatment group model was constructed with the subcutaneous injection of cyproterone acetate in PCOS mice. The expression of pyroptosis-related protein in ovarian GCs was detected to explore the alleviating effect of CYA on the pyroptosis of ovarian GCs in PCOS mice. Thirdly, KGN cells-i.e., from the human GC line-were cultured with dihydrotestosterone, CYA, and <i>ERN1</i> (IRE1α gene) small interfering RNA in vitro to explore whether CYA can alleviate the activation of the IRE1α signaling pathway and ameliorate the hyperandrogenemia-induced pyroptosis of PCOS ovarian GCs. Results: The expression of pyroptosis-related proteins was significantly increased in ovarian GCs of PCOS patients with HA as the main clinical manifestation, and in the PCOS mouse model induced by DHEA. After treatment with CYA, the expression of pyroptosis-related proteins in the ovarian GCs of mice was significantly lower than that in PCOS mice. In vitro experiments showed that CYA could ameliorate KGN cells’ pyroptosis by alleviating the activation of the IRE1α signaling pathway. Conclusion: This study showed that CYA could ameliorate the activation of the IRE1α signaling pathway in mouse GCs and KGN cells, and also alleviate pyroptosis in ovarian GCs. This study provides a new mechanism and evidential support for CYA in the treatment of PCOS patients. |
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| spelling | doaj.art-269061ac83d149308a905e713c0155992023-11-24T13:23:01ZengMDPI AGBiology2079-77372022-12-011112176110.3390/biology11121761Cyproterone Acetate Mediates IRE1α Signaling Pathway to Alleviate Pyroptosis of Ovarian Granulosa Cells Induced by HyperandrogenYan Zhang0Xianguo Xie1Yabo Ma2Changzheng Du3Yuan Jiao4Guoliang Xia5Jinrui Xu6Yi Yang7Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western, School of Life Sciences, Ningxia University, Yinchuan 750021, ChinaKey Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western, School of Life Sciences, Ningxia University, Yinchuan 750021, ChinaKey Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western, School of Life Sciences, Ningxia University, Yinchuan 750021, ChinaKey Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western, School of Life Sciences, Ningxia University, Yinchuan 750021, ChinaThe Second Clinical College of China Medical University, 77 Puhe Road, Shenbei New District, Shenyang 110000, ChinaKey Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western, School of Life Sciences, Ningxia University, Yinchuan 750021, ChinaKey Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western, School of Life Sciences, Ningxia University, Yinchuan 750021, ChinaKey Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western, School of Life Sciences, Ningxia University, Yinchuan 750021, ChinaObjective: Hyperandrogenemia (HA) is the main pathophysiological change that takes place in polycystic ovary syndrome (PCOS). Cyproterone acetate (CYA) is a drug commonly used to reduce androgen in patients with PCOS. Long-term and continuous exposure to HA can cause ovarian granulosa cells (GCs), pyroptotic death, and follicular dysfunction in PCOS mice. The aim of this study was to investigate whether CYA could ameliorate the hyperandrogenemia-induced pyroptosis of PCOS ovarian GCs by alleviating the activation of the IRE1α signaling pathway. Methods: Firstly, thirty PCOS patients with HA as their main clinical manifestation were selected as the study group, and thirty non-PCOS patients were selected as the control group. The GCs and follicular fluid of the patients were collected, and the expression of pyroptosis-related proteins was detected. Secondly, a PCOS mouse model induced by dehydroepiandrosterone (DHEA) was constructed, and the treatment group model was constructed with the subcutaneous injection of cyproterone acetate in PCOS mice. The expression of pyroptosis-related protein in ovarian GCs was detected to explore the alleviating effect of CYA on the pyroptosis of ovarian GCs in PCOS mice. Thirdly, KGN cells-i.e., from the human GC line-were cultured with dihydrotestosterone, CYA, and <i>ERN1</i> (IRE1α gene) small interfering RNA in vitro to explore whether CYA can alleviate the activation of the IRE1α signaling pathway and ameliorate the hyperandrogenemia-induced pyroptosis of PCOS ovarian GCs. Results: The expression of pyroptosis-related proteins was significantly increased in ovarian GCs of PCOS patients with HA as the main clinical manifestation, and in the PCOS mouse model induced by DHEA. After treatment with CYA, the expression of pyroptosis-related proteins in the ovarian GCs of mice was significantly lower than that in PCOS mice. In vitro experiments showed that CYA could ameliorate KGN cells’ pyroptosis by alleviating the activation of the IRE1α signaling pathway. Conclusion: This study showed that CYA could ameliorate the activation of the IRE1α signaling pathway in mouse GCs and KGN cells, and also alleviate pyroptosis in ovarian GCs. This study provides a new mechanism and evidential support for CYA in the treatment of PCOS patients.https://www.mdpi.com/2079-7737/11/12/1761hyperandrogenemiapyroptosisgranulosa cellsIRE1α signaling pathway |
| spellingShingle | Yan Zhang Xianguo Xie Yabo Ma Changzheng Du Yuan Jiao Guoliang Xia Jinrui Xu Yi Yang Cyproterone Acetate Mediates IRE1α Signaling Pathway to Alleviate Pyroptosis of Ovarian Granulosa Cells Induced by Hyperandrogen Biology hyperandrogenemia pyroptosis granulosa cells IRE1α signaling pathway |
| title | Cyproterone Acetate Mediates IRE1α Signaling Pathway to Alleviate Pyroptosis of Ovarian Granulosa Cells Induced by Hyperandrogen |
| title_full | Cyproterone Acetate Mediates IRE1α Signaling Pathway to Alleviate Pyroptosis of Ovarian Granulosa Cells Induced by Hyperandrogen |
| title_fullStr | Cyproterone Acetate Mediates IRE1α Signaling Pathway to Alleviate Pyroptosis of Ovarian Granulosa Cells Induced by Hyperandrogen |
| title_full_unstemmed | Cyproterone Acetate Mediates IRE1α Signaling Pathway to Alleviate Pyroptosis of Ovarian Granulosa Cells Induced by Hyperandrogen |
| title_short | Cyproterone Acetate Mediates IRE1α Signaling Pathway to Alleviate Pyroptosis of Ovarian Granulosa Cells Induced by Hyperandrogen |
| title_sort | cyproterone acetate mediates ire1α signaling pathway to alleviate pyroptosis of ovarian granulosa cells induced by hyperandrogen |
| topic | hyperandrogenemia pyroptosis granulosa cells IRE1α signaling pathway |
| url | https://www.mdpi.com/2079-7737/11/12/1761 |
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