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Modulation of the RAC1/MAPK/ERK signalling pathway by farnesyl diphosphate synthase regulates granulosa cells proliferation in polycystic ovary syndrome

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Abstract

Polycystic ovary syndrome (PCOS) is a complex gynaecological endocrine disease that occurs in women of childbearing age. The pathogenesis of PCOS is still unclear and further exploration is needed. Here, proteomic analysis indicated that the expression of farnesyl diphosphate synthase (FDPS) protein in ovarian tissue of PCOS mice was significantly decreased. The purpose of this study is to investigate the relationship between potential biomarkers of PCOS and granulosa cells (GCs) function. The mechanisms by which FDPS affected the proliferation of granulosa cells were also explored both in vitro and in vivo. We found that knockdown of FDPS inhibited the proliferation of KGN (human ovarian granulosa cell line), while overexpression of FDPS had the opposite effect. FDPS activated Rac1 (Rac Family Small GTPase 1) activity and regulated MAPK/ERK signalling pathway, which affecting the proliferation of KGN cells significantly. In addition, treatment with the adeno-associated virus (AAV)-FDPS reverses the dehydroepiandrosterone (DHEA)-induced PCOS-phenotype in mice. Our data indicated that FDPS could regulate the proliferation of ovarian GCs by modulating MAPK/ERK (mitogen-activated protein kinase/extracellular regulated protein kinases) pathway via activating Rac1 activity. These findings suggest that FDPS could be of great value for the regulation of ovarian granulosa cell function and the treatment of PCOS.

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Availability of data and materials

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Abbreviations

PCOS:

Polycystic ovary syndrome

FDPS:

Farnesyl diphosphate synthase

AAV:

Adeno-associated virus

KGN:

Human ovarian granulosa cell line

RAC1:

Rac family small GTPase 1

MAPK:

Mitogen-activated protein kinase

ERK:

Extracellular regulated protein kinases

LH:

Luteinizing hormone

FSH:

Follicle-stimulating hormone

GnRH:

Gonadotropin-releasing hormone

AMH:

Anti-Mullerian hormone

DHEA:

Dehydroepiandrosterone

GCs:

Granulosa cells

DEPs:

Differentially expressed proteins

GO:

Gene ontology

References

  1. Stener-Victorin E, Deng Q. Epigenetic inheritance of polycystic ovary syndrome - challenges and opportunities for treatment. Nat Rev Endocrinol. 2021;17(9):521–33. https://doi.org/10.1038/s41574-021-00517-x.

    Article  PubMed  Google Scholar 

  2. Yuan X, Hu T, Zhao H, Huang Y, Ye R, Lin J, et al. Brown adipose tissue transplantation ameliorates polycystic ovary syndrome. Proc Natl Acad Sci U S A. 2016;113(10):2708–13. https://doi.org/10.1073/pnas.1523236113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Franks S, Stark J, Hardy K. Follicle dynamics and anovulation in polycystic ovary syndrome. Hum Reprod Update. 2008;14(4):367–78. https://doi.org/10.1093/humupd/dmn015.

    Article  CAS  PubMed  Google Scholar 

  4. Palomba S, Daolio J, La Sala GB. Oocyte competence in women with polycystic ovary syndrome. Trends Endocrinol Metab. 2017;28(3):186–98. https://doi.org/10.1016/j.tem.2016.11.008.

    Article  CAS  PubMed  Google Scholar 

  5. Khan MJ, Ullah A, Basit S. Genetic basis of polycystic ovary syndrome (PCOS): current perspectives. Appl Clin Genet. 2019;12(249):260. https://doi.org/10.2147/TACG.S200341.

    Article  Google Scholar 

  6. Bednarska S, Siejka A. The pathogenesis and treatment of polycystic ovary syndrome: what’s new? Adv Clin Exp Med. 2017;26:359–67. https://doi.org/10.17219/acem/59380.

    Article  PubMed  Google Scholar 

  7. Chen M, He C, Zhu K, Chen Z, Meng Z, Jiang X, et al. Resveratrol ameliorates polycystic ovary syndrome via transzonal projections within oocyte-granulosa cell communication. Theranostics. 2022;12(2):782–95. https://doi.org/10.7150/thno.67167.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ji R, Jia F, Chen X, Gao Y, Yang J. Carnosol inhibits KGN cells oxidative stress and apoptosis and attenuates polycystic ovary syndrome phenotypes in mice through Keap1-mediated Nrf2/HO-1 activation. Phytother Res. 2023;37(4):1405–21. https://doi.org/10.1002/ptr.7749.

    Article  CAS  PubMed  Google Scholar 

  9. Salehi R, Asare-Werehene M, Wyse BA, Abedini A, Pan B, Gutsol A, et al. Granulosa cell-derived miR-379-5p regulates macrophage polarization in polycystic ovarian syndrome. Front Immunol. 2023;14:1104550. https://doi.org/10.3389/fimmu.2023.1104550.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Munakata Y, Kawahara-Miki R, Shiratsuki S, Tasaki H, Itami N, Shirasuna K, et al. Gene expression patterns in granulosa cells and oocytes at various stages of follicle development as well as in in vitro grown oocyte-and-granulosa cell complexes. J Reprod Dev. 2016;62(4):359–66. https://doi.org/10.1262/jrd.2016-022.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Jiang Q, Miao R, Wang Y, Wang W, Zhao D, Niu Y, et al. ANGPTL4 inhibits granulosa cell proliferation in polycystic ovary syndrome by EGFR/JAK1/STAT3-mediated induction of p21. FASEB J. 2023;37(2): e22693. https://doi.org/10.1096/fj.202201246RR.

    Article  CAS  PubMed  Google Scholar 

  12. Dinsdale NL, Crespi BJ. Endometriosis and polycystic ovary syndrome are diametric disorders. Evol Appl. 2021;14(7):1693–715. https://doi.org/10.1111/eva.13244.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Tang T, Jiao J, Li D, Sun G, Lin L, Wang C, et al. The function of BAP18 on modulation of androgen receptor action in luteinized granulosa cells from normal weight women with and without PCOS. Mol Cell Endocrinol. 2021;527:111228. https://doi.org/10.1016/j.mce.2021.111228.

    Article  CAS  PubMed  Google Scholar 

  14. Nasri F, Zare M, Doroudchi M, Gharesi-Fard B. Proteome analysis of CD4(+) T cells reveals differentially expressed proteins in infertile polycystic ovary syndrome patients. Endocr Metab Immune Disord Drug Targets. 2021;21(11):1998–2004. https://doi.org/10.2174/1871530320666201119152323.

    Article  CAS  PubMed  Google Scholar 

  15. Manousopoulou A, Al-Daghri NM, Sabico S, Garay-Baquero DJ, Teng J, Alenad A, et al. Polycystic ovary syndrome and insulin physiology: an observational quantitative serum proteomics study in adolescent, normal-weight females. Proteomics Clin Appl. 2019;13(5): e1800184. https://doi.org/10.1002/prca.201800184.

    Article  CAS  PubMed  Google Scholar 

  16. Zhang C, Jin DD, Wang XY, Lou L, Yang J. Key enzymes for the mevalonate pathway in the cardiovascular system. J Cardiovasc Pharmacol. 2021;77(2):142–52. https://doi.org/10.1097/fjc.0000000000000952.

    Article  CAS  PubMed  Google Scholar 

  17. Seshacharyulu P, Rachagani S, Muniyan S, Siddiqui JA, Cruz E, Sharma S, et al. FDPS cooperates with PTEN loss to promote prostate cancer progression through modulation of small GTPases/AKT axis. Oncogene. 2019;38(26):5265–80. https://doi.org/10.1038/s41388-019-0791-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Qu F, Wang FF, Lu XE, Dong MY, Sheng JZ, Lv PP, et al. Altered aquaporin expression in women with polycystic ovary syndrome: hyperandrogenism in follicular fluid inhibits aquaporin-9 in granulosa cells through the phosphatidylinositol 3-kinase pathway. Hum Reprod. 2010;25(6):1441–50. https://doi.org/10.1093/humrep/deq078.

    Article  CAS  PubMed  Google Scholar 

  19. Ji X, Ye Y, Wang L, Liu S, Dong X. PDE4 inhibitor Roflumilast modulates inflammation and lipid accumulation in PCOS mice to improve ovarian function and reduce DHEA-induced granulosa cell apoptosis in vitro. Drug Dev Res. 2023. https://doi.org/10.1002/ddr.22027.

    Article  PubMed  Google Scholar 

  20. Zhang Q, Ren J, Wang F, Li M, Pan M, Zhang H, et al. Chinese herbal medicine alleviates the pathogenesis of polycystic ovary syndrome by improving oxidative stress and glucose metabolism via mitochondrial Sirtuin 3 signaling. Phytomedicine. 2023;109:154556. https://doi.org/10.1016/j.phymed.2022.154556.

    Article  CAS  PubMed  Google Scholar 

  21. Yang T, Huang Y, Zhou Y, Chen S, Wang H, Hu Y, et al. Simultaneous quantification of oestrogens and androgens in the serum of patients with benign prostatic hyperplasia by liquid chromatography-Tandem mass spectrometry. Andrologia. 2020;52(7): e13611. https://doi.org/10.1111/and.13611.

    Article  CAS  PubMed  Google Scholar 

  22. Geng X, Zhao J, Huang J, Li S, Chu W, Wang WS, et al. lnc-MAP3K13-7:1 Inhibits Ovarian GC Proliferation in PCOS via DNMT1 Downregulation-Mediated CDKN1A Promoter Hypomethylation. Mol Ther. 2021;29(3):1279–93. https://doi.org/10.1016/j.ymthe.2020.11.018.

    Article  CAS  PubMed  Google Scholar 

  23. Alesi S, Ee C, Moran LJ, Rao V, Mousa A. Nutritional Supplements and Complementary Therapies in Polycystic Ovary Syndrome. Adv Nutr. 2022;13(4):1243–66. https://doi.org/10.1093/advances/nmab141.

    Article  CAS  PubMed  Google Scholar 

  24. Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril. 2004;81:19–25. https://doi.org/10.1016/j.fertnstert.2003.10.004.

    Article  Google Scholar 

  25. Zheng Q, Li Y, Zhang D, Cui X, Dai K, Yang Y, et al. ANP promotes proliferation and inhibits apoptosis of ovarian granulosa cells by NPRA/PGRMC1/EGFR complex and improves ovary functions of PCOS rats. Cell Death Dis. 2017;8(10): e3145. https://doi.org/10.1038/cddis.2017.494.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Dehghan Z, Mohammadi-Yeganeh S, Sameni M, Mirmotalebisohi SA, Zali H, Salehi M. Repurposing new drug candidates and identifying crucial molecules underlying PCOS pathogenesis based on bioinformatics analysis. Daru. 2021;29(2):353–66. https://doi.org/10.1007/s40199-021-00413-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wang X, Zhang X, Chen Y, Zhao C, Zhou W, Chen W, et al. Cardiac-specific deletion of FDPS induces cardiac remodeling and dysfunction by enhancing the activity of small GTP-binding proteins. J Pathol. 2021;255(4):438–50. https://doi.org/10.1002/path.5789.

    Article  CAS  PubMed  Google Scholar 

  28. Estienne A, Mellouk N, Bongrani A, Plotton I, Langer I, Ramé C, et al. Involvement of chemerin and CMKLR1 in the progesterone decrease by PCOS granulosa cells. Reproduction. 2021;162(6):427–36. https://doi.org/10.1530/rep-21-0265.

    Article  CAS  PubMed  Google Scholar 

  29. Lin L, Wang L. Knockdown of DPP4 promotes the proliferation and the activation of the CREB/aromatase pathway in ovarian granulosa cells. Mol Med Rep. 2022;25:73. https://doi.org/10.3892/mmr.2022.1258.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Jin T, Lu J, Lv Q, Gong Y, Feng Z, Ying H, et al. Farnesyl diphosphate synthase regulated endothelial proliferation and autophagy during rat pulmonary arterial hypertension induced by monocrotaline. Mol Med. 2022;28(1):94. https://doi.org/10.1186/s10020-022-00511-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Szkopińska A, Płochocka D. Farnesyl diphosphate synthase; regulation of product specificity. Acta Biochim Pol. 2005;52(1):45–55.

    Article  PubMed  Google Scholar 

  32. Ubba V, Soni UK, Chadchan S, Maurya VK, Kumar V, Maurya R, et al. RHOG-DOCK1-RAC1 signaling axis is perturbed in DHEA-induced polycystic ovary in rat model. Reprod Sci. 2017;24(5):738–52. https://doi.org/10.1177/1933719116669057.

    Article  CAS  PubMed  Google Scholar 

  33. Du CQ, Liu XW, Zeng GZ, Jin HF, Tang LJ. Inhibition of farnesyl pyrophosphate synthase attenuates angiotensin II-induced fibrotic responses in vascular smooth muscle cells. Int J Mol Med. 2015;35(6):1767–72. https://doi.org/10.3892/ijmm.2015.2166.

    Article  CAS  PubMed  Google Scholar 

  34. Maurya VK, Sangappa C, Kumar V, Mahfooz S, Singh A, Rajender S, et al. Expression and activity of Rac1 is negatively affected in the dehydroepiandrosterone induced polycystic ovary of mouse. J Ovarian Res. 2014;7:32. https://doi.org/10.1186/1757-2215-7-32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Abate M, Laezza C, Pisanti S, Torelli G, Seneca V, Catapano G, et al. Deregulated expression and activity of farnesyl diphosphate synthase (FDPS) in glioblastoma. Sci Rep. 2017;7(1):14123. https://doi.org/10.1038/s41598-017-14495-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Peng Y, Yang X, Luo X, Liu C, Cao X, Wang H, et al. Novel mechanisms underlying anti-polycystic ovary like syndrome effects of electroacupuncture in rats: suppressing SREBP1 to mitigate insulin resistance, mitochondrial dysfunction and oxidative stress. Biol Res. 2020;53(1):50. https://doi.org/10.1186/s40659-020-00317-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank all volunteers in this study for their cooperation and the support of gynaecologists in Xuzhou Central Hospital.

Funding

This work was supported by the Natural Science Foundation of China [No. 82173883]; the Science and Technology Foundation of Xuzhou [No. KC22469]; the Natural Science Foundation of the Jiangsu Higher Education Institutions of China [No. 18KJA350002]; the Natural Science Foundation of Jiangsu Province [No. BK20181470]; the Provincial Commission of Health and Family Planning in Jiangsu Province [No. H2017079]; and the Science and Technology Planning Project of Jiangsu Province [No. BE2019636].

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Author notes

  1. Xiaoli Guo and Yijuan Cao have contributed equally to this work.

Authors and Affiliations

  1. Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, College of Pharmacy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, China

    Xiaoli Guo, Linna Chen, Wenqiang Lv & Xueyan Zhou

  2. Department of Obstetrics and Gynecology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University, 199 South Jiefang Road, Xuzhou, 221004, China

    Yijuan Cao, Qing He, Qing Wang, Jingbo Zhang & Bei Zhang

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  1. Xiaoli Guo
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Contributions

Xl G and Yj C were involved in the experimental design and performed the data analysis. Xl G and Yj C contributed equally to this work and were considered co-first authors. Q H, NL C, Q W, Bj Z and Wq L were equally involved in experimental design, performing the experiments, and data analysis. Xl G edited the manuscript. B Z and Xy Z contributed scientific ideas and revised the manuscript. B Z and Xy Z led the entire study as corresponding authors. All the authors have read and approved the final manuscript.

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Correspondence to Bei Zhang or Xueyan Zhou.

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The study was registered in the Chinese Clinical Trial Register in 2022 (ChiCTR2300067599) and was performed in accordance with the Helsinki Declaration; the protocol was approved by the Ethics Committee of Xuzhou Central Hospital. The animal study was approved by the Animal Ethics Committee of Xuzhou Medical University (Approval No. 202301T004) and followed the National Institutes of Health guidelines.

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Guo, X., Cao, Y., He, Q. et al. Modulation of the RAC1/MAPK/ERK signalling pathway by farnesyl diphosphate synthase regulates granulosa cells proliferation in polycystic ovary syndrome. Human Cell 37, 689–703 (2024). https://doi.org/10.1007/s13577-024-01050-5

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