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

Wang, Rongli; Wang, Lijun; Wang, Lihui; Cui, Zhiwei; Cheng, Feiyan; Wang, Wei; Yang, Xinyuan

doi:10.3389/fendo.2022.890623

Cited by 9 publications

(10 citation statements)

References 49 publications

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“…Other studies demonstrated that NRF2-mediated autophagy through the P62-KEAP1 pathway [ 16 , 17 ] and our previous study declared that activation of autophagy protected cisplatin-injured cells [ 14 ]. This evidence prompted us to investigate whether NRF2 mediates the autophagy in cisplatin-injured cells.…”

Section: Resultsmentioning

confidence: 95%

“…Our previous study demonstrated that FGF2 protected cisplatin-injured cells through promoting autophagy [ 14 ]. And results in this study suggested that NRF2 also played a protective role in cisplatin-induced cells through activating autophagy pathway.…”

Section: Resultsmentioning

confidence: 99%

“…In our previous studies, we found menstrual-derived stem cells and conditional medium derived from these cells exerted reparative effects on damaged ovaries partially by secreting FGF2 [ 7 ]. We also found FGF2 could promote autophagy to protect cisplatin-induced granulosa cells [ 14 ]. Recent research reported that FGF2 could accelerate oxidative diabetic wound healing [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

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FGF2 Rescued Cisplatin-Injured Granulosa Cells through the NRF2-Autophagy Pathway

Wang,

Cheng,

Pan

et al. 2023

IJMS

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Premature ovarian failure (POF) is a complicated disorder related to the apoptosis of granulosa cells. The incidence of chemotherapy-associated POF is rising dramatically owing to the increasing proportion of cancer in adolescents. According to previous studies, oxidative stress caused by chemotherapeutic agents plays an important role in the development of POF. However, the exact effects of nuclear factor-erythroid 2-related factor2 (NRF2), a pivotal anti-oxidative factor, are still unknown in chemotherapy-associated POF. Firstly, we manipulated NRF2 expressions on a genetic or pharmaceutical level in cisplatin-injured granulosa cell models. The results indicate that the increasing NRF2 in cisplatin-injured cells was just compensatory and not enough to resist the accumulated stress. Upregulation of NRF2 could protect granulosa cells against cisplatin via elevating autophagic level by using an autophagic activator (rapamycin) and inhibitor (chloroquine). Additionally, exogenous FGF2 exerted a protective role by increasing NRF2 expression and promoting its nuclear translocation. Meanwhile, the results in cisplatin-POF mice models were consistent with what was found in injured cells. In conclusion, our research proved that FGF2 rescued cisplatin-injured granulosa cells through the NRF2-autophagy pathway and might provide a possible alternative treatment choice by targeting NRF2 for POF patients who are intolerant or unsuitable to FGF2.

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Section: Resultsmentioning

confidence: 95%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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FGF2 Rescued Cisplatin-Injured Granulosa Cells through the NRF2-Autophagy Pathway

Wang,

Cheng,

Pan

et al. 2023

IJMS

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“…Many researches have validated that the occurrence of POF is tightly associated with the apoptosis of granulosa cells [ 25 , 31 , 32 ]. And it was reported that autophagy is also involved [ 33 – 35 ]. However, little is known about ferroptosis, another prevalent form of programmed cell death, whether participates in the pathogenesis of POF.…”

Section: Discussionmentioning

confidence: 99%

Endometrial stem cells alleviate cisplatin-induced ferroptosis of granulosa cells by regulating Nrf2 expression

Pan,

Wang,

Cheng

et al. 2024

Reprod Biol Endocrinol

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Background Premature ovarian failure (POF) caused by cisplatin is a severe and intractable sequela for young women with cancer who received chemotherapy. Cisplatin causes the dysfunction of granulosa cells and mainly leads to but is not limited to its apoptosis and autophagy. Ferroptosis has been also reported to participate, while little is known about it. Our previous experiment has demonstrated that endometrial stem cells (EnSCs) can repair cisplatin-injured granulosa cells. However, it is still unclear whether EnSCs can play a repair role by acting on ferroptosis. Methods Western blotting and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) were applied to detect the expression levels of ferroptosis-related genes. CCK-8 and 5-Ethynyl-2’-deoxyuridine (EdU) assays were used to evaluate cell viability. Transmission electron microscopy (TEM) was performed to detect ferroptosis in morphology. And the extent of ferroptosis was assessed by ROS, GPx, GSSG and MDA indicators. In vivo, ovarian morphology was presented by HE staining and the protein expression in ovarian tissue was detected by immunohistochemistry. Results Our results showed that ferroptosis could occur in cisplatin-injured granulosa cells. Ferroptosis inhibitor ferrostatin-1 (Fer-1) and EnSCs partly restored cell viability and mitigated the damage of cisplatin to granulosa cells by inhibiting ferroptosis. Moreover, the repair potential of EnSCs can be markedly blocked by ML385. Conclusion Our study demonstrated that cisplatin could induce ferroptosis in granulosa cells, while EnSCs could inhibit ferroptosis and thus exert repair effects on the cisplatin-induced injury model both in vivo and in vitro. Meanwhile, Nrf2 was validated to participate in this regulatory process and played an essential role.

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“…Total RNA was isolated from KGN cell line using Trizol reagent (Invitrogen, CO., Carlsbad, CA, USA), the concentration and purity of the RNA were detected, and complementary DNA (cDNA) was synthesisd as our previously described [34] . qRT-PCR was performed using SYBR Premix ExTaq™ (Takara) on the StepOne Real -Time PCR System (Applied Biosystems, USA) and the relative expression levels of the target genes were analyzed by the 2 −ΔΔCt method.…”

Section: Rna Extraction and Qrt-pcr Assaymentioning

confidence: 99%

FTO attenuates the cytotoxicity of cisplatin on KGN cells by regulating the Hippo/YAP1 signaling pathway

Wang,

Yang

2023

Preprint

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Premature ovarian failure (POF) is a devastating condition for women under 40 years old. Chemotherapy, especially the cisplatin, has been demonstrated to promote the apoptosis of granulosa cell in primary and secondary follicle, and then leading to POF. Our previous studies have demonstrated that fat mass- and obesity-associated (FTO) plays an essential role in protecting granulosa cells from cisplatin-induced cytotoxicity. Various studies have suggested that the Hippo/YAP signaling pathway plays a significant role in regulating cell apoptosis and proliferation. And YAP1 was the main downstream target of Hippo signaling pathway, which was negatively regulated by Hippo signaling pathway. However, whether the Hippo/YAP signaling pathway is involved in the protective effect of FTO on granulosa cells remains unclear. In this study, we found that, after cisplatin treatment, the apoptosis of granulosa cells increased in a concentration-dependent manner, accompanied by the downregulation of FTO and YAP1. Furthermore, overexpression of FTO decreased cisplatin induced granulosa cell apoptosis, inhibited the Hippo/YAP kinase cascade induced phosphorylation of YAP1, and promoted the entry of YAP1 into the nuclei. The downstream targets of YAP1 (CTGF, CYR61, and ANKRD1) were also increased. Si-RNA mediated down-regulation of FTO promoted cisplatin induced granulosa cells apoptosis, activated the Hippo/YAP kinase cascade, and inhibited the YAP1 entry into nuclei. And these effects were completely reversed by the small molecule inhibitor of YAP1-verteporfin (VP). Co-ip assay showed that there was a strong interaction between proteins of FTO and YAP1.Taken together, these data suggested that FTO-YAP1 played a positive role in regulated injured granulosa cells proliferation, induced by cisplatin.

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

Cited by 9 publications

References 49 publications

FGF2 Rescued Cisplatin-Injured Granulosa Cells through the NRF2-Autophagy Pathway

FGF2 Rescued Cisplatin-Injured Granulosa Cells through the NRF2-Autophagy Pathway

Endometrial stem cells alleviate cisplatin-induced ferroptosis of granulosa cells by regulating Nrf2 expression

FTO attenuates the cytotoxicity of cisplatin on KGN cells by regulating the Hippo/YAP1 signaling pathway

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