17βE2 promotes cell proliferation in endometriosis by decreasing PTEN via NFκB-dependent pathway

Zhang, Hui; Zhao, Xianxian; Liu, Shu; Li, Jijun; Wen, Zhiyuan; Li, Mingjiang

doi:10.1016/j.mce.2009.11.009

Cited by 81 publications

(59 citation statements)

References 52 publications

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“…12,45 Moreover, AKT activity is higher in ovarian endometriosis than in normal endometrium, 46 and it has been postulated that estrogens might be one of the factors responsible for the high AKT activation in endometriotic cells. 17 However, if estrogens activate AKT in epithelial endometriotic cells, 17 this phenomenon is less clear in stromal endometriotic cells. 15 Indeed, in the stromal cells, a specific estrogen receptor antagonist fails to antagonize the effects of estradiol and exerts a stimulatory effect on AKT phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

“…13,14 Little is known about the role of other potentially proproliferative pathways in endometriosis. The PI3K/mTOR/AKT pathway has been found to be activated in ovarian endometriosis [15][16][17] and has been implicated in the pathogenesis of ovarian cancer. 17 To date, however, no study has explored this pathway in DIE, and the involvement of this pathway has never been explored in vivo.…”

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confidence: 99%

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The mTOR/AKT Inhibitor Temsirolimus Prevents Deep Infiltrating Endometriosis in Mice

Leconte

Nicco

Ngô

et al. 2011

The American Journal of Pathology

100

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Deep infiltrating endometriosis (DIE) is a particular clinical and histological entity of endometriosis responsible for chronic pelvic pain and infertility. Here we characterize the proliferative phenotype of DIE cells, to explore the cellular and molecular mechanisms that could explain their aggressive potential. In addition, the inhibition of mTOR/AKT pathway was tested, as a potential treatment of DIE. Included were 22 patients with DIE and 12 control patients without endometriosis. Epithelial and stromal cells were extracted from biopsies of eutopic endometrium and deep infiltrating endometriotic nodules from patients with DIE. Cell proliferation was determined by thymidine incorporation. Oxidative stress was assayed by spectrofluorometry. The ERK and mTOR/AKT pathways were analyzed in vitro by Western blot and for AKT in vivo in a mouse model of DIE. The proliferation rate of eutopic endometrial cells and of deep infiltrating endometriotic cells from DIE patients was higher than that of endometrial cells from controls. The hyperproliferative phenotype of endometriotic cells was associated with an increase in endogenous oxidative stress, and with activation of the ERK and mTOR/AKT pathways. mTOR/AKT inhibition by temsirolimus decreased endometriotic cell proliferation both in vitro and in vivo in a mouse model of DIE. Blocking the mTOR/AKT pathway offers new prospects for the treatment of DIE.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

The mTOR/AKT Inhibitor Temsirolimus Prevents Deep Infiltrating Endometriosis in Mice

Leconte

Nicco

Ngô

et al. 2011

The American Journal of Pathology

100

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“…Another study highlighted the link between high levels of phosphorylated AKT (S473) an increased Survivin expression, suggesting that Akt permits cell survival and apoptosis avoidance (Zhang et al 2009). According to its hormone-driven nature, E 2 was shown to promote endometriotic cell proliferation through the reduced expression of PTEN and the subsequent activation of AKT (Zhang et al 2010).…”

Section: Endometriosismentioning

confidence: 99%

“…The NFkB pathway also seems to be entwined in the hormonal response as well as survival mechanisms in which AKT is involved (Grund et al 2008, Zhang et al 2010, Capp et al 2011. It seems highly plausible that these proteins are all part of a complexly intertwined signaling network as links have been extensively demonstrated among the mTOR complex, the PTEN/PI3K/Akt axis, and the NFkB signaling pathway.…”

Section: Endometriosismentioning

confidence: 99%

Expression, activation, and role of AKT isoforms in the uterus

Fabi¹,

Asselin²

2014

Reproduction

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The three isoforms of AKT: AKT1, AKT2, and AKT3, are crucial regulators of both normal and pathological cellular processes. Each of these isoforms exhibits a high level of homology and functional redundancy with each other. However, while being highly similar and structurally homologous, a rising amount of evidence is showing that each isoform possesses specific targets as well as preferential subcellular localization. The role of AKT has been studied extensively in reproductive processes, but isoform-specific roles are yet to be fully understood. This review will focus on the role of AKT in the uterus and its function in processes related to cell death and proliferation such as embryo implantation, decidualization, endometriosis, and endometrial cancer in an isoform-centric manner. In this review, we will cover the activation of AKT in various settings, localization of isoforms in subcellular compartments, and the effect of isoform expression on cellular processes. To fully understand the dynamic molecular processes taking place in the uterus, it is crucial that we better understand the physiological role of AKT isoforms as well as their function in the emergence of diseases.Reproduction (2014) 148 R85-R95

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“…EMS shares some common features with cancer. For instance, the loss of the tumor suppressor PTEN in endometrial cancer was well-established in 2010 (17) and decreased PTEN expression has also been reported in the eutopic and ectopic endometrial of patients with EMS as well (18). In women of reproductive age, EMS mainly involves the ovary (2); an endometriotic cyst of ovary is the most common type of EMS.…”

Section: Discussionmentioning

confidence: 99%

Methylation status and protein expression of RASSF1A in endometriosis

Zhang²,

Zhang

et al. 2016

Oncology Letters

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Abstract. Ras association domain family 1A (RASSF1A) gene inactivation by promoter hypermethylation is a common event in the development of a variety of types of human cancer. Accumulated evidence has demonstrated that DNA methylation serve a critical role in the pathogenesis of endometriosis. The aim of the present study was to analyze the methylation status and protein expression of RASSF1A in endometriosis (EMS). The ectopic and corresponding eutopic endometrium tissues were collected from 45 women with EMS (EMS group) and normal endometrium tissues from 20 women without EMS (control group). The methylation status of RASSF1A was examined by methylation specific polymerase chain reaction (MSP). Immunohistochemistry was performed to measure RASSF1A protein level in endometrium tissues. In normal endometrium samples, RASSF1A protein expression was significantly higher at the secretory phase than the proliferative phase. RASSF1A protein expression in the ectopic endometrium tissues and eutopic endometrium tissues were significantly reduced than in normal endometrium (P<0.05). The frequency of aberrant methylation of RASSF1A was 55.56% in ectopic endometrium and 33.33% in paired eutopic endometrium, whereas such methylation was not detected in normal endometrium. Moreover, RASSF1A promoter hypermethylation was frequently associated with reduced expression of RASSF1A, and was common in advanced stage in ectopic endometrium of EMS. Epigenetic inactivation of RASSF1A through aberrant promoter methylation may be important in the formation and progression of EMS, and assessment of RASSF1A methylation status in eutopic endometrium may be a potentially useful biomarker to enhance the early detection of EMS.

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17βE2 promotes cell proliferation in endometriosis by decreasing PTEN via NFκB-dependent pathway

Cited by 81 publications

References 52 publications

The mTOR/AKT Inhibitor Temsirolimus Prevents Deep Infiltrating Endometriosis in Mice

The mTOR/AKT Inhibitor Temsirolimus Prevents Deep Infiltrating Endometriosis in Mice

Expression, activation, and role of AKT isoforms in the uterus

Methylation status and protein expression of RASSF1A in endometriosis

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