FTO protects human granulosa cells from chemotherapy-induced cytotoxicity

Wang, Rongli; Wang, Wei; Wang, Lijun; Yuan, Linnan; Cheng, Feiyan; Guan, Xin; Zheng, Nini; Yang, Xinyuan

doi:10.1186/s12958-022-00911-8

Cited by 19 publications

(19 citation statements)

References 61 publications

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“…A large number of gap junctions exist between GCs and oocytes through which nutrients and signaling molecules are transported into the oocyte to promote oocyte nuclear versus cytoplasmic maturation 55 . Death of GCs can inhibit oocyte and follicle development, and promote POI triggered by follicular atresia 56 . Therefore, to further validate our experiments, we cultured GCs in vitro.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of ferroptosis in a rat model of premature ovarian insufficiency induced by cisplatin

Cheng

et al. 2023

Sci Rep

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Ferroptosis is widely present in fibrosis-related diseases. The basic pathology of premature ovarian insufficiency (POI) involves ovarian tissue fibrosis, and there are currently fewer relevant studies addressing the association between ferroptosis and POI. This study aimed to demonstrate that ferroptosis induced by cisplatin (CDDP) caused ovarian tissue fibrosis, leading to POI. Vitamin E (VE), a ferroptosis inhibitor, could repair damaged ovarian function. CDDP was used to establish a rat model of POI, and VE was administered to reverse the reproductive toxicity of CDDP. Ovarian function was assessed by histological section staining, follicle counts, sex hormone levels, as well as fertility assays. The extent of ferroptosis was assessed by transmission electron microscopy (TEM), malondialdehyde (MDA), Perls staining. CCK-8, Ethynyl-2-Deoxyuridine (EdU), and scratch assays were used to determine the effect of CDDP and VE on ovarian granulosa cell (GC) viability. Western blot, quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry were performed to evaluate ferroptosis-related molecular changes. Our results showed that CDDP caused follicle development disorders and ovarian tissue fibrosis, the levels of sex hormones suggested impaired ovarian function, and VE could reverse the reproductive toxicity of CDDP. The results of TEM, MDA and Perls staining suggested that the typical mitochondrial signature of ferroptosis was altered in ovarian GCs from the CDDP group, with significantly higher levels of lipid peroxidation and significant iron deposition in ovarian tissue, whereas VE mitigated the extent of ferroptosis. Molecular experiments then confirmed that the ferroptosis-related molecules acetyl CoA synthetase long chain family member 4 (ACSl4), 15-lipoxygenase-1 (ALOX15), solute carrier family 7 member 11 (SLC7A11), and glutathione peroxidase 4 (GPX4) were differentially expressed in each group. In summary, our study preliminarily demonstrated that CDDP may promote GCs to undergo ferroptosis, cause follicle development disorders, ovarian tissue fibrosis, and induce POI by regulating the expression of ACSl4, ALOX15, SLC7A11, and GPX4, while VE improved impaired ovarian function.

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Section: Discussionmentioning

confidence: 99%

Mechanism of ferroptosis in a rat model of premature ovarian insufficiency induced by cisplatin

Cheng

et al. 2023

Sci Rep

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“…Therefore, it is of great clinical significance to further explore the mechanisms underlying POF and discover more effective and safer therapeutic targets. Based on the reproductive toxicity of chemotherapy drugs, chemotherapy is an important cause of POF [47]. The ovaries, as organs with dual reproductive and endocrine functions, are crucial for multiple systems, including fertility.…”

Section: Discussionmentioning

confidence: 99%

Metformin protects ovarian granulosa cells in chemotherapy-induced premature ovarian failure mice through AMPK/PPAR-γ/SIRT1 pathway

Yang,

Tang,

Yao

et al. 2023

Preprint

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The incidence of premature ovarian failure (POF) is progressively escalating, with chemotherapy drugs identified as a significant contributing factor. Our study demonstrates that chemotherapy drugs can induce abnormal inflammation and oxidative stress within the ovary, resulting in damage to granulosa cells (GCs), which may be a significant cause of POF. Furthermore, numerous studies have reported Metformin (MET) has various beneficial effects, including anti-aging, anti-oxidative stress, and anti-inflammatory. Hence, the objective of this study is to investigate whether MET can be utilized for the treatment of chemotherapy-induced ovarian inflammation and the improvement of premature aging. Our vivo experiments conducted on animal models indicate that oral administration of MET ameliorates chemotherapy-induced ovarian damage and alleviates hormonal disruption in mice with POF by reducing inflammatory and oxidative stress-related harm. In our in vitro experiments, we aimed to simulate the inflammatory condition present within the ovary by indirectly co-culturing primary GCs with M1 macrophages. We observed injury to GCs caused by M1 macrophage supernatants was mitigated by treatment with MET. To validate the potential pathways involved in the action of MET, we observed that MET ameliorated GCs damage induced by M1 macrophages, possibly through the activation of the AMPK/PPAR-γ/SIRT1 pathway.

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“…Furthermore, our previous studies have demonstrated that FGF2 secreted from menstrual-derived stem cells (MenSCs) reduced granulosa cell apoptosis in POF mice ( 17 ). In addition, MenSCs promote the recovery of chemotherapy-induced POF mice ovarian and cisplatin-induced injured granulosa cells via regulating the expression of FTO ( 49 ). In this study, we found that FGF2 increases FTO expression in injured granulosa cells.…”

Section: Discussionmentioning

confidence: 99%

FGF2 Is Protective Towards Cisplatin-Induced KGN Cell Toxicity by Promoting FTO Expression and Autophagy

Wang

et al. 2022

Front. Endocrinol.

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It is widely known that chemotherapy-induced apoptosis of granulosa was the main reason for premature ovarian failure (POF). In addition, accumulating evidence has demonstrated that autophagy was involved in it. Studies before have reported that fibroblast growth factor-2 (FGF2) could attenuate cell death via regulating autophagy. In our previous study, FGF2 could decrease granulosa cell apoptosis in cisplatin-induced POF mice. Furthermore, obesity-associated protein [fat mass and obesity-associated protein (FTO)], which decreased significantly in POF mice, could inhibit cell apoptosis via activating autophagy. Moreover, downregulation of FTO could decrease the expression of paracrine factor FGF2. However, the relationship between FTO and FGF2 in granulosa cell autophagy is still unknown. In the present study, Cell Counting Kit-8 (CCK-8) and 5‐ethynyl‐2‐deoxyuridine (EdU) assays showed that exogenous addition of FGF2 could promote cisplatin-induced injured granulosa cell proliferation. Western blotting indicated that FGF2 could inhibit apoptosis of injured granulosa cells via autophagy. Inhibition of autophagy by chemicals suppressed the effect of FGF2 and promoted injured cell apoptosis. In addition, the expression of FTO was decreased in injured cells, and FGF2 addition could reverse it. Overexpression of FTO reduced injured cell apoptosis via activating the autophagy process. Our findings indicated that FGF2 activates autophagy by regulating the expression of FTO, thereby reducing the apoptosis of the injured cells.

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FTO protects human granulosa cells from chemotherapy-induced cytotoxicity

Cited by 19 publications

References 61 publications

Mechanism of ferroptosis in a rat model of premature ovarian insufficiency induced by cisplatin

Mechanism of ferroptosis in a rat model of premature ovarian insufficiency induced by cisplatin

Metformin protects ovarian granulosa cells in chemotherapy-induced premature ovarian failure mice through AMPK/PPAR-γ/SIRT1 pathway

FGF2 Is Protective Towards Cisplatin-Induced KGN Cell Toxicity by Promoting FTO Expression and Autophagy

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