Leydig cell tumorigenesis - implication of G-protein coupled membrane estrogen receptor, peroxisome proliferator-activated receptor and xenoestrogen exposure. In vivo and in vitro appraisal

Górowska-Wójtowicz, Ewelina; Duliban, Michał; Kudrycka, M.; Dutka, Przemysław; Pawlicki, Piotr; Miłoń, Agnieszka; Zarzycka, Marta; Placha, Wojciech; Kotula–Balak, Małgorzata; Ptak, Anna; Wolski, Jan; Bilińska, Barbara

doi:10.1016/j.tice.2019.08.001

Cited by 19 publications

(24 citation statements)

References 55 publications

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“…In addition, adipokine signaling proteins were examined to define the role these hormones play and whether there is a potential interaction between adipokines and aromatase. This study is a continuation of our prior reported data [28,29] and provides further knowledge on the biology of Leydig cell tumors.…”

Section: Introductionsupporting

confidence: 67%

“…What is more, in human Leydig cell tumors, varying expression patterns of both ER and non-canonical G-protein coupled estrogen receptor were observed [14,28,29,60]. These findings suggest that altered estrogen signalization with canonical and non-canonical estrogen receptors is involved in the biochemical properties of Leydig cell tumors and it should be under consideration as an important treatment target.…”

Section: Discussionmentioning

confidence: 87%

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Interstitial Leydig Cell Tumorigenesis—Leptin and Adiponectin Signaling in Relation to Aromatase Expression in the Human Testis

Duliban

Górowska-Wójtowicz

Tworzydło

et al. 2020

IJMS

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Although epidemiological studies from the last years report an increase in the incidences of Leydig cell tumors (previously thought to be a rare disease), the biochemical characteristics of that tumor important for understanding its etiology, diagnosis, and therapy still remains not completely characterized. Our prior studies reported G-protein coupled estrogen receptor signaling and estrogen level disturbances in Leydig cell tumors. In addition, we found that expressions of multi-level-acting lipid balance- and steroidogenesis–controlling proteins including peroxisome proliferator-activated receptor are altered in this tumor. In order to get deeper into the other molecular mechanisms that regulate lipid homeostasis in the Leydig cell tumor, here we investigate the presence and expression of newly-described hormones responsible for lipid homeostasis balancing (leptin and adiponectin), together with expression of estrogen synthase (aromatase). Samples of Leydig cell tumors (n = 20) were obtained from patients (31–45 years old) and used for light and transmission electron microscopic, western blotting, and immunohistochemical analyses. In addition, body mass index (BMI) was calculated. In tumor mass, abundant lipid accumulation in Leydig cells and various alterations of Leydig cell shape, as well as the presence of adipocyte-like cells, were observed. Marked lipid content and various lipid droplet size, especially in obese patients, may indicate alterations in lipid homeostasis, lipid processing, and steroidogenic organelle function in response to interstitial tissue pathological changes. We revealed significantly increased expression of leptin, adiponectin and their receptors, as well as aromatase in Leydig cell tumors in comparison to control. The majority of patients (n = 13) were overweight as indicated by their BMI. Moreover, a significant increase in expression of phospholipase C (PLC), and kinases Raf, ERK which are part of adipokine transductional pathways, was demonstrated. These data expand our previous findings suggesting that in human Leydig cell tumors, estrogen level and signaling, together with lipid status, are related to each other. Increased BMI may contribute to certain biochemical characteristics and function of the Leydig cell in infertile patients with a tumor. In addition, altered adipokine-estrogen microenvironment can have an effect on proliferation, growth, and metastasis of tumor cells. We report here various targets (receptors, enzymes, hormones) controlling lipid balance and estrogen action in Leydig cell tumors indicating their possible usefulness for diagnostics and therapy.

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Section: Introductionsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 87%

Interstitial Leydig Cell Tumorigenesis—Leptin and Adiponectin Signaling in Relation to Aromatase Expression in the Human Testis

Duliban

Górowska-Wójtowicz

Tworzydło

et al. 2020

IJMS

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“…An innovative aspect in the study of GPER role in Leydig cell tumors is the functional interaction among GPER and other receptors. Recently, Gorowska-Wojtowicz and colleagues [133] examined Rago and colleagues demonstrated that seminomas and embryonal carcinomas had a positive ERβ1 and ERβ2 immunoreactivity, while ERα signal was undetectable [120]. Indeed, in a seminoma cell line which lacks ERα expression, ERβ activation has been shown to be associated with cell necrosis and autophagy [121].…”

Section: Gper Role In Testicular Tumorsmentioning

confidence: 99%

“…An innovative aspect in the study of GPER role in Leydig cell tumors is the functional interaction among GPER and other receptors. Recently, Gorowska-Wojtowicz and colleagues [133] examined mainly the relationship between GPER and PPARs expression and estrogen level after several xenoestrogens treatment. The authors demonstrated that in tissues from mice MA-10 xenograft models and in MA-10 cells treated with BPA and TCBPA, PPARα expression was increased while that of GPER, PPARβ and PPARγ was decreased together with estradiol production.…”

Section: Gper Role In Testicular Tumorsmentioning

confidence: 99%

“…Testicular Physiology Testicular Tumors SPG GPER activation induces proliferation [84][85][86] GPER is overexpressed in seminoma and embryonal carcinoma [119], (whereas ERα is missing [120]) GPER mediates estrogen and xenoestrogen-dependent proliferation in seminomas [123][124][125]128,129] SPT GPER activation induces apoptosis [31,32,88] RS GPER activation induces apoptosis [30] LC GPER is involved in: LC morphology and function [38] LCT [where ERα is overexpressed]: GPER activation decrease cell proliferation and induces apoptosis [130] Xenoestrogens decrease GPER expression favoring LCT progression [133] GPER is involved in LCT control of lipid metabolism and steroidogenesis (interaction with PPAR) [134] LC androgens production [40] LC lipophagy inhibition [43] LC miRNA biogenesis [49] LC development and function [PPAR crosstalk] [46] SC GPER activation induces proliferation in immature testis [65][66][67][68] Sertoli cell tumors: GPER is expressed but the role has been not identified. In interstitial compartment, GPER appears to play an important role in regulating estrogen-dependent lipid homeostasis and testosterone biosynthesis that occur in Leydig cells.…”

Section: Cell Typesmentioning

confidence: 99%

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Role of GPER-Mediated Signaling in Testicular Functions and Tumorigenesis

Chimento

Luca

Nocito

et al. 2020

Cells

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Estrogen signaling plays important roles in testicular functions and tumorigenesis. Fifteen years ago, it was discovered that a member of the G protein-coupled receptor family, GPR30, which binds also with high affinity to estradiol and is responsible, in part, for the rapid non-genomic actions of estrogens. GPR30, renamed as GPER, was detected in several tissues including germ cells (spermatogonia, spermatocytes, spermatids) and somatic cells (Sertoli and Leydig cells). In our previous review published in 2014, we summarized studies that evidenced a role of GPER signaling in mediating estrogen action during spermatogenesis and testis development. In addition, we evidenced that GPER seems to be involved in modulating estrogen-dependent testicular cancer cell growth; however, the effects on cell survival and proliferation depend on specific cell type. In this review, we update the knowledge obtained in the last years on GPER roles in regulating physiological functions of testicular cells and its involvement in neoplastic transformation of both germ and somatic cells. In particular, we will focus our attention on crosstalk among GPER signaling, classical estrogen receptors and other nuclear receptors involved in testis physiology regulation.

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Tetrachlorobisphenol A and bisphenol AF induced cell migration by activating PI3K/Akt signaling pathway via G protein‐coupled estrogen receptor 1 in SK‐BR‐3 cells

Lei

et al. 2022

Environmental Toxicology

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Different subtypes of breast cancer express positively G protein‐coupled estrogen receptor 1 (GPER1). Our previous studies found that tetrachlorobisphenol A (TCBPA) and bisphenol AF (BPAF) significantly promoted SK‐BR‐3 cell proliferation by activating GPER1‐regulated signals. The present study further investigated the effects of TCBPA and BPAF on the migration of SK‐BR‐3 cells and examined the role of phosphatidylinositol 3‐kinase‐protein kinase B (PI3K/Akt) and its downstream signal targets in this process. We found that low‐concentration BPAF and TCBPA markedly accelerated the migration of SK‐BR‐3 cells and elevated the mRNA levels of target genes associated with PI3K/Akt and mitogen‐activated protein kinase (MAPK) signals. TCBPA‐ and BPAF‐induced upregulation of target genes was significantly reduced by GPER1 inhibitor G15, the PI3K/Akt inhibitor wortmannin (WM), and the epidermal growth factor receptor (EGFR) inhibitor ZD1839 (ZD). G15 and WM also decreased cell migration induced by TCBPA and BPAF. The findings revealed that TCBPA and BPAF promoted SK‐BR‐3 cell migration ability by activating PI3K/Akt signaling pathway via GPER1‐EGFR.

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Leydig cell tumorigenesis - implication of G-protein coupled membrane estrogen receptor, peroxisome proliferator-activated receptor and xenoestrogen exposure. In vivo and in vitro appraisal

Cited by 19 publications

References 55 publications

Interstitial Leydig Cell Tumorigenesis—Leptin and Adiponectin Signaling in Relation to Aromatase Expression in the Human Testis

Interstitial Leydig Cell Tumorigenesis—Leptin and Adiponectin Signaling in Relation to Aromatase Expression in the Human Testis

Role of GPER-Mediated Signaling in Testicular Functions and Tumorigenesis

Tetrachlorobisphenol A and bisphenol AF induced cell migration by activating PI3K/Akt signaling pathway via G protein‐coupled estrogen receptor 1 in SK‐BR‐3 cells

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