Abstract
Research question
What is the effect of vitamin D3 (1,25(OH)2D3) on proliferation, cell cycle and apoptosis of endometrial stromal cells (ESC) in
endometriotic patients?
Design
ESC isolated from 10 women with endometriosis and 10 healthy controls were treated
with 1,25(OH)2D3. The proliferation of control endometrial stromal cells (CESC), eutopic endometrial
stromal cells (EuESC) and ectopic endometrial stromal cells (EESC) was analysed 72 h
after the treatment using methyl thiazolyl tetrazolium assay. Propidium iodide staining
and flow cytometry were used to determine the cell cycle distribution in ESC. Annexin
V/propidium iodide double staining was used to evaluate apoptosis in ESC.
Results
In the presence of oestrogen, 1,25(OH)2D3 treatment inhibited the proliferation of ESC from all three origins (P = 0.009 for CESC, P = 0.005 for EuESC and P < 0.001 for EESC). The percentage of S phase cells in EESC was higher than in EuESC
and CESC (P = 0.002 and P = 0.001, respectively). The percentage of S phase cells in EuESC was higher than
in CESC (P = 0.005). The percentage of G1 phase cells in EESC was lower than that of EuESC and
CESC (P = 0.003 and P = 0.002, respectively) and the percentage of G1 phase cells in EuESC was lower than
that of CESC (P = 0.007). Moreover, 1,25(OH)2D3 inhibited cell cycle regardless of cell type (P = 0.002 in EESC, P = 0.001 in EuESC and P = 0.014 in CESC), but in the absence of oestrogen, inhibited cell cycle only in EuESC
(P = 0.012).
Conclusions
Although 1,25(OH)2D3 increased apoptotic and necrotic cells and decreased live cells in the EuESC and
EESC, it did not affect apoptosis in CESC and only increased necrotic cells. These
findings indicate that 1,25(OH)2D3 potentially has a growth-inhibiting and pro-apoptotic effect on ESC from endometriotic
patients.
Keywords
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References
- Apoptosis in endometriosis.Gynecol. Obstet. Invest. 2009; 68: 217-223
- 1,25-dihydroxyvitamin D3 regulates expression of sex steroid receptors in human uterine fibroid cells.J. Clin. Endocrinol. Metab. 2015; 100: E572-E582
- Revised American Society for Reproductive Medicine classification of endometriosis: 1996.Fertil. Steril. 1997; 67: 817-821
- Resveratrol reduces the expression of insulin-like growth factor-1 and hepatocyte growth factor in stromal cells of women with endometriosis compared with nonendometriotic women.Phytother. Res. 2019; 33: 1044-1054
- 1,25-dihydroxyvitamin D3 and cisplatin synergistically induce apoptosis and cell cycle arrest in gastric cancer cells.Int. J. Mol. Med. 2014; 33: 1177-1184
- Policing cancer: vitamin D arrests the cell cycle.Int. J. Molec. Sci. 2020; 21: 9296
- Vitamin D inhibits myometrial and leiomyoma cell proliferation in vitro.Fertil. Steril. 2009; 91: 1919-1925
- Vitamin D and human health: lessons from vitamin D receptor null mice.Endocr. Rev. 2008; 29: 726-776
- Vitamin D and endometrium: a systematic review of a neglected area of research.Int. J. Mol. Sci. 2018; 19: 2320
- Platelet-derived growth factor (PDGF), epidermal growth factor (EGF), and EGF and PDGF beta-receptors in human endometrial tissue: localization and in vitro action.Endocrinology. 1992; 130: 2373-2385
- Downregulation of CD36 results in reduced phagocytic ability of peritoneal macrophages of women with endometriosis.J. Pathol. 2009; 219: 232-241
- Pleiotrophin (PTN) and midkine (MK) mRNA expression in eutopic and ectopic endometrium in advanced stage endometriosis.Molec. Hum. Reprod. 2002; 8: 350-355
- Advances in the management of endometriosis: an update for clinicians.Hum. Reprod. Update. 2006; 12: 179-189
- Estrogen signaling in the proliferative endometrium: implications in endometriosis.Rev. Assoc. Med. Bras. (1992). 2016; 62: 72-77
- Eutopic and ectopic stromal cells from patients with endometriosis exhibit differential invasive, adhesive, and proliferative behavior.Fertil. Steril. 2013; 100: 761-769
- 1,25-dihydroxy vitamin D3 modulates endometriosis-related features of human endometriotic stromal cells.Am. J. Reprod. Immunol. 2016; 75: 461-473
- Vitamin D deficiency as a risk factor for endometriosis in Iranian women.J. Reprod. Immunol. 2021; 143103266
- Mammalian G1 cyclins.Curr. Opin. Cell Biol. 1994; 6: 842-846
- Current and emerging treatment options for endometriosis.Expert Opin. Pharmacother. 2018; 19: 1109-1125
- Effects of vitamin D3 and its chemical analogs on the growth of Hodgkin's lymphoma, in vitro.BMC Res. Notes. 2019; 12: 216
- Endometriosis.Lancet. 2004; 364: 1789-1799
- Cell cycle arrest and apoptosis induced by 1α,25(OH)2D3 and TX 527 in Kaposi sarcoma is VDR dependent.J. Steroid. Biochem. Mol. Biol. 2014; 144: 197-200
- Vitamin D3 action within the ovary – an updated review.Physiol. Res. 2020; 69: 371-378
- Recurrence of endometriosis and its control.Hum. Reprod. Update. 2009; 15: 441-461
- Vitamin D3 inhibits expression and activities of matrix metalloproteinase-2 and -9 in human uterine fibroid cells.Hum. Reprod. 2013; 28: 2407-2416
- Antitumor effects and mechanisms of 1,25(OH)2D3 in the Pfeiffer diffuse large B lymphoma cell line.Mol. Med. Rep. 2019; 20: 5064-5074
- Apoptosis in human endometrium and endometriosis.Hum. Reprod. Update. 2004; 10: 29-38
- The effect of 1,25-dihydroxyvitamin D3 on lymphoma cell lines and expression of vitamin D receptor in lymphoma.Br. J. Cancer. 1993; 68: 668-672
- miR-503, a microRNA epigenetically repressed in endometriosis, induces apoptosis and cell-cycle arrest and inhibits cell proliferation, angiogenesis, and contractility of human ovarian endometriotic stromal cells.Hum. Reprod. 2016; 31: 2587-2597
- Vitamin D: a millenium perspective.J. Cell Biochem. 2003; 88: 296-307
- Growth mechanisms of endometriotic cells in implanted places: a review.Gynecol. Endocrinol. 2012; 28: 562-567
- Apoptosis and bcl-2 expression in normal human endometrium, endometriosis and adenomyosis.Hum. Reprod. 1998; 13: 3496-3502
- Molecular actions of vitamin D in reproductive cell biology.Reproduction. 2017; 153: R29-R42
- Endometrial cells from women with endometriosis have increased adhesion and proliferative capacity in response to extracellular matrix components: towards a mechanistic model for endometriosis progression.Hum. Reprod. 2007; 22: 3139-3147
- The potential therapeutic benefits of vitamin D in the treatment of estrogen receptor positive breast cancer.Steroids. 2012; 77: 1107-1112
- Anti-proliferative and pro-apoptotic properties of 3-bromoacetoxy calcidiol in high-risk neuroblastoma.Chem. Biol. Drug Des. 2007; 70: 302-310
- Vitamin D and fertility: a systematic review.Eur. J. Endocrinol. 2012; 166: 765-778
- The anti-inflammatory effects of vitamin D in tumorigenesis.Int. J. Mol. Sci. 2018; 1: 2736
- Homologous and heterologous regulation of 1,25-dihydroxyvitamin D-3 receptor mRNA levels in human osteosarcoma cells.Biochim. Biophys. Acta, Gene. Struct. Expr. 1991; 1088: 111-118
- Steroid regulation of menstrual bleeding and endometrial repair.Rev. Endocr. Metab. Disord. 2012; 13: 253-263
- Apoptosis and expression of Bcl-2 and Bax in eutopic endometrium from women with endometriosis.Fertil. Steril. 2000; 74: 760-766
- Expression of cell-cycle regulatory proteins in endometrial carcinomas: correlations with hormone receptor status and clinicopathologic parameters.J. Cancer Res. Clin. Oncol. 2001; 127: 537-544
- Effects of 1,25-dihydroxy vitamin D3 on endometriosis.J. Clin. Endocrinol. Metab. 2016; 101: 2371-2379
- Differential effects of 1,25-dihydroxyvitamin D3 and tetradecanoylphorbol acetate on cell cycle and apoptosis of MCF-7 cells and a vitamin D3-resistant variant.Endocrinology. 1997; 138: 4690-4698
- Endometriotic cells are resistant to interferon-γ-induced cell growth inhibition and apoptosis: a possible mechanism involved in the pathogenesis of endometriosis.Molec. Hum. Reprod. 2005; 11: 29-34
- The expression of estrogen receptors as well as GREB1, c-MYC, and cyclin D1, estrogen-regulated genes implicated in proliferation, is increased in peritoneal endometriosis.Fertil. Steril. 2012; 98: 1200-1208
- Estrogen-dependent cyclin E-cdk2 activation through p21 redistribution.Mol. Cell Biol. 1997; 17: 4059-4069
- Sulindac and vitamin D3 synergically inhibit proliferation of MCF-7 breast cancer cell through AMPK/Akt /β-catenin axis in vitro.Cell Biochem. Funct. 2021; 39: 991-997
- Subcellular distribution of estrogen receptor and progesterone receptor with and without specific ligand.Am. J. Pathol. 1989; 135: 857-864
- Peritoneal endometriosis due to the menstrual dissemination of endometrial tissue into the peritoneal cavity.Am. J. Obstet. Gynecol. 1927; 14: 422-469
- Vitamin D-mediated apoptosis in cancer and obesity.Horm. Mol. Biol. Clin. Investig. 2014; 20: 43-49
- Vitamin D inhibits proliferation of human uterine leiomyoma cells via catechol-O-methyltransferase.Fertil. Steril. 2011; 95: 247-253
- Endometrial anomalies in women with endometriosis.Ann. N. Y. Acad. Sci. 2001; 943: 131-147
- Estrogen-induced proliferation of normal endometrial glandular cells is initiated by transcriptional activation of cyclin D1 via binding of c-Jun to an AP-1 sequence.Oncogene. 2004; 23: 8603-8610
- Involvement of cyclin-dependent kinase inhibitor p27Kip1 in growth inhibition of endometrium in the secretory phase and of hyperplastic endometrium treated with progesterone.Mol. Hum. Reprod. 1998; 4: 899-905
- Membrane initiated estrogen signaling in breast cancer.Biol. Reprod. 2006; 75: 9-16
- High expression levels of cyclin B1 and Polo-like kinase 1 in ectopic endometrial cells associated with abnormal cell cycle regulation of endometriosis.Fertil. Steril. 2009; 91: 979-987
- Apoptosis and endometriosis.Front. Biosci. (Elite Ed). 2011; 3: 648-662
- Endometriosis is a chronic systemic disease: clinical challenges and novel innovations.Lancet. 2021; 397: 839-852
- Increased mitogen-activated protein kinase kinase/extracellularly regulated kinase activity in human endometrial stromal fibroblasts of women with endometriosis reduces 3′,5′-cyclic adenosine 5′-monophosphate inhibition of cyclin D1.Endocrinology. 2009; 150: 4701-4712
- Endometriosis: pathogenesis and treatment.Nat. Rev. Endocrinol. 2014; 10: 261-275
- The cell cycle and cancer.J. Pathol. 2012; 226: 352-364
- Abnormal activation of Ras/Raf/MAPK and RhoA/ROCKII signalling pathways in eutopic endometrial stromal cells of patients with endometriosis.Hum. Reprod. 2011; 26: 885-897
- The expression status of G protein-coupled receptor GPR30 is associated with the clinical characteristics of endometriosis.Endocr. Res. 2013; 38: 223-231
- 17βE2 promotes cell proliferation in endometriosis by decreasing PTEN via NFκB-dependent pathway.Mol. Cell. Endocrinol. 2010; 317: 31-43
Biography
Ali-Akbar Delbandi was born in Tehran in 1974 and graduated in immunology at Mashhad University of Medical Sciences. He has been a faculty member at the Iran University of Medical Sciences since 2014. His research focuses on reproductive immunology with an emphasis on endometriosis.
Key message
The effects of 1,25(OH)2D3 (active vitamin D) on endometriosis were assessed; it prevented the proliferation of endometriotic stromal cells, and simultaneously induced apoptosis. Increased sensitivity of endometriotic cells to apoptosis might prevent the distribution and implantation of endometriotic stromal cells to ectopic sites. Vitamin D might prevent the progression of endometriosis by reducing the proliferation of these cells.
Article info
Publication history
Published online: November 17, 2022
Accepted:
November 14,
2022
Received in revised form:
October 24,
2022
Received:
August 13,
2022
Declaration: The authors report no financial or commercial conflicts of interest.Identification
Copyright
© 2022 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.
