1,25-Dihydroxyvitamin D3 Alleviates Hyperandrogen-induced Ferroptosis in KGN Cells

Overview

Journal Hormones (Athens)

Specialty Endocrinology

Date 2023 Mar 8

PMID 36884209

Authors

Yijie Jiang

Jianshu Yang

Ke Du

Kaiming Luo

Xin Yuan

Fei Hua

Affiliations

Soon will be listed here.

Abstract

Purpose: Hyperandrogenism, one of the most frequent causes of anovulation in women, increases the risk of metabolic disorders in patients with polycystic ovary syndrome (PCOS). Ferroptosis, characterized by iron-dependent lipid peroxidation, has provided new insight into the progression of PCOS. 1,25-dihydroxyvitamin D3 (1,25D3) may play a role in reproduction because its receptor, VDR, which contributes to the inhibition of oxidative stress, is primarily located in the nuclei of granulosa cells. This study has therefore investigated whether 1,25D3 and hyperandrogenism affect granulosa-like tumor cells (KGN cells) through ferroptosis.

Methods: KGN cells were treated with dehydroepiandrosterone (DHEA) or pretreated with 1,25D3. Cell viability was evaluated with the cell counting kit-8 (CCK-8) assay. The mRNA and protein expression levels of ferroptosis-related molecules, including glutathione peroxidase 4 (GPX4), solute carrier family 7 member (SLC7A11), and long-chain acyl-CoA synthetase 4 (ACSL4), were assessed via qRT-PCR and western blot. The concentration of malondialdehyde (MDA) was measured by ELISA. The rates of reactive oxygen species (ROS) production and lipid peroxidation were assessed via photometric methods.

Results: Decreased cell viability, suppression of GPX4 and SLC7A11 expression, increased expression of ACSL4, elevated levels of MDA, accumulation of ROS, and increased lipid peroxidation, which are changes representative of ferroptosis, were observed in KGN cells after treatment with DHEA. Pretreatment with 1,25D3 in KGN cells significantly prevented these changes.

Conclusions: Our findings demonstrate that 1,25D3 attenuates hyperandrogen-induced ferroptosis of KGN cells. This finding might lead to new insights into the pathophysiology and therapy of PCOS and provides new evidence for the treatment of PCOS with 1,25D3.

Citing Articles

Research progress of cysteine transporter SLC7A11 in endocrine and metabolic diseases.

Chen J, Yuan M, Wang J Mol Biol Rep. 2025; 52(1):185.

PMID: 39899147 DOI: 10.1007/s11033-024-10193-5.

Broadening horizons: the role of ferroptosis in polycystic ovary syndrome.

Wang M, Zhang B, Ma S, Xu Y, Zhao D, Zhang J Front Endocrinol (Lausanne). 2024; 15:1390013.

PMID: 39157678 PMC: 11327064. DOI: 10.3389/fendo.2024.1390013.

High coverage of targeted lipidomics revealed lipid changes in the follicular fluid of patients with insulin-resistant polycystic ovary syndrome and a positive correlation between plasmalogens and oocyte quality.

Zhang M, Wang Y, Di J, Zhang X, Liu Y, Zhang Y Front Endocrinol (Lausanne). 2024; 15:1414289.

PMID: 38904043 PMC: 11187234. DOI: 10.3389/fendo.2024.1414289.

Mitigating bisphenol A-induced apoptosis in KGN cells: the therapeutic role of 1,25-dihydroxyvitamin D through upregulation of PGC-1α expression and inhibition of the mitochondrial cytochrome c pathway.

Tang L, Du K, Luo K, Wang L, Hua F Hormones (Athens). 2024; 23(3):363-374.

PMID: 38421590 PMC: 11436470. DOI: 10.1007/s42000-024-00539-w.

References

Wang D, Wang T, Wang R, Zhang X, Wang L, Xiang Z . Suppression of p66Shc prevents hyperandrogenism-induced ovarian oxidative stress and fibrosis. J Transl Med. 2020; 18(1):84. PMC: 7027222. DOI: 10.1186/s12967-020-02249-4. View

Zhang Y, Hu M, Jia W, Liu G, Zhang J, Wang B . Hyperandrogenism and insulin resistance modulate gravid uterine and placental ferroptosis in PCOS-like rats. J Endocrinol. 2020; 246(3):247-263. DOI: 10.1530/JOE-20-0155. View

Smith E, Alvarez J, Kearns M, Hao L, Sloan J, Konrad R . High-dose vitamin D reduces circulating hepcidin concentrations: A pilot, randomized, double-blind, placebo-controlled trial in healthy adults. Clin Nutr. 2016; 36(4):980-985. PMC: 5191989. DOI: 10.1016/j.clnu.2016.06.015. View

Tang D, Kang R, Vanden Berghe T, Vandenabeele P, Kroemer G . The molecular machinery of regulated cell death. Cell Res. 2019; 29(5):347-364. PMC: 6796845. DOI: 10.1038/s41422-019-0164-5. View

Bacchetta J, Zaritsky J, Sea J, Chun R, Lisse T, Zavala K . Suppression of iron-regulatory hepcidin by vitamin D. J Am Soc Nephrol. 2013; 25(3):564-72. PMC: 3935584. DOI: 10.1681/ASN.2013040355. View

Jiang X, Stockwell B, Conrad M . Ferroptosis: mechanisms, biology and role in disease. Nat Rev Mol Cell Biol. 2021; 22(4):266-282. PMC: 8142022. DOI: 10.1038/s41580-020-00324-8. View

Lee C, Wang J, Chou K, Hsu M . 1,25-Dihydroxyvitamin D modulates the effects of sublethal BPA on mitochondrial function via activating PI3K-Akt pathway and 17β-estradiol secretion in rat granulosa cells. J Steroid Biochem Mol Biol. 2018; 185:200-211. DOI: 10.1016/j.jsbmb.2018.09.002. View

Wang L, Liu Y, Du T, Yang H, Lei L, Guo M . ATF3 promotes erastin-induced ferroptosis by suppressing system Xc. Cell Death Differ. 2019; 27(2):662-675. PMC: 7206049. DOI: 10.1038/s41418-019-0380-z. View

Li Y, Zheng Q, Sun D, Cui X, Chen S, Bulbul A . Dehydroepiandrosterone stimulates inflammation and impairs ovarian functions of polycystic ovary syndrome. J Cell Physiol. 2018; 234(5):7435-7447. DOI: 10.1002/jcp.27501. View

10.

Masjedi F, Keshtgar S, Zal F, Talaei-Khozani T, Sameti S, Fallahi S . Effects of vitamin D on steroidogenesis, reactive oxygen species production, and enzymatic antioxidant defense in human granulosa cells of normal and polycystic ovaries. J Steroid Biochem Mol Biol. 2019; 197:105521. DOI: 10.1016/j.jsbmb.2019.105521. View

11.

Thomson R, Spedding S, Buckley J . Vitamin D in the aetiology and management of polycystic ovary syndrome. Clin Endocrinol (Oxf). 2012; 77(3):343-50. DOI: 10.1111/j.1365-2265.2012.04434.x. View

12.

Dixon S, Lemberg K, Lamprecht M, Skouta R, Zaitsev E, Gleason C . Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012; 149(5):1060-72. PMC: 3367386. DOI: 10.1016/j.cell.2012.03.042. View

13.

Merhi Z, Doswell A, Krebs K, Cipolla M . Vitamin D alters genes involved in follicular development and steroidogenesis in human cumulus granulosa cells. J Clin Endocrinol Metab. 2014; 99(6):E1137-45. PMC: 4037738. DOI: 10.1210/jc.2013-4161. View

14.

Sinha A, Hollingsworth K, Ball S, Cheetham T . Improving the vitamin D status of vitamin D deficient adults is associated with improved mitochondrial oxidative function in skeletal muscle. J Clin Endocrinol Metab. 2013; 98(3):E509-13. DOI: 10.1210/jc.2012-3592. View

15.

Norman R, Dewailly D, Legro R, Hickey T . Polycystic ovary syndrome. Lancet. 2007; 370(9588):685-97. DOI: 10.1016/S0140-6736(07)61345-2. View

16.

Suda T, Masuyama R, Bouillon R, Carmeliet G . Physiological functions of vitamin D: what we have learned from global and conditional VDR knockout mouse studies. Curr Opin Pharmacol. 2015; 22:87-99. DOI: 10.1016/j.coph.2015.04.001. View

17.

Johansson J, Feng Y, Shao R, Lonn M, Billig H, Stener-Victorin E . Intense electroacupuncture normalizes insulin sensitivity, increases muscle GLUT4 content, and improves lipid profile in a rat model of polycystic ovary syndrome. Am J Physiol Endocrinol Metab. 2010; 299(4):E551-9. DOI: 10.1152/ajpendo.00323.2010. View

18.

Hu Z, Zhang H, Yi B, Yang S, Liu J, Hu J . VDR activation attenuate cisplatin induced AKI by inhibiting ferroptosis. Cell Death Dis. 2020; 11(1):73. PMC: 6989512. DOI: 10.1038/s41419-020-2256-z. View

19.

Lizneva D, Suturina L, Walker W, Brakta S, Gavrilova-Jordan L, Azziz R . Criteria, prevalence, and phenotypes of polycystic ovary syndrome. Fertil Steril. 2016; 106(1):6-15. DOI: 10.1016/j.fertnstert.2016.05.003. View

20.

Goodarzi M, Dumesic D, Chazenbalk G, Azziz R . Polycystic ovary syndrome: etiology, pathogenesis and diagnosis. Nat Rev Endocrinol. 2011; 7(4):219-31. DOI: 10.1038/nrendo.2010.217. View