Progesterone-Mediated Non-Classical Signaling

Garg, Deepika; Ng, Sinnie Sin Man; Baig, K. Maravet; Driggers, Paul H.; Segars, James H.

doi:10.1016/j.tem.2017.05.006

Cited by 106 publications

(78 citation statements)

References 93 publications

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“…Non-genomic effect of estrogen via cell surface membrane bound mERs, Ca 2+ signalling and kinases activated. E2: estrogen, ER: estrogen receptor, mER (mER-X, mERx): membrane bound estrogen receptor (-X and x), Gq-mER: G-protein coupled membrane bound estrogen receptor, GPER/GPR30: G-protein coupled estrogen receptor 1 / G-protein coupled receptor 30, TF: transcription factor, GF: growth factor progesterone signalling, but rapid progesterone effects are also mediated by membrane-bound PRs, cytoplasmic PRs and receptor-independent signalling via various signal transduction pathways, called 'non-classical' progesterone signalling, as reviewed in detail by Garg and colleagues [40] and summarized in Fig. 2 [40][41][42].…”

Section: Determinants Of Progesterone Effect On Tissuesmentioning

confidence: 99%

“…However, there were significant differences between the two trials effecting the lymph node positivity and tamoxifen application. Although the original RCT results seemed to be [40][41][42] conflicting, and even now no clear-cut conclusion can be drawn, trials of the last decade, including extended followup studies of HABITS and the Stockholm Trial have seemed to indicate an increased recurrance risk of breast cancer after different HRT regimens, with the relative risk (RR) of recurrence varying between 2.0 to 3.6 [50,51]. In the extended follow-up of HABITS, Holmberg and colleagues found a RR of recurrence of 2.4 (n=442, mean HRT duration 24 months, follow-up 5 years, recurrence 22.2% HRT user vs. 8.0% non-user) [52].…”

Section: Breast Cancermentioning

confidence: 99%

See 1 more Smart Citation

Hormone Replacement Therapy in Cancer Survivors – Review of the Literature

Deli

Orosz

Jakab

2019

Pathol. Oncol. Res.

135

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Rapid advance in oncology leads to increasing survival of oncologic patients. More and more of them live long enough to reach either the natural age of menopause or, as a side effect of their oncotherapy, experience the cessation of gonadal function, leading to premature ovarian insufficiency, with disturbing vasomotor symtoms and long-term negative cardiovascular and skeletal effects. Thus, an ever increasing number of cancer survivors search endocrinologic help in the form of hormone replacement therapy (HRT). The misinterpretation of the WHI (Women's Health Initiative) Study has lead to an irrational fear of female hormone replacement, both by the general population and medical professionals. It has seemed the logical and safe conclusion to many physicians to avoid HRT, supposing that this attitude definitely causes no harm, whereas the decision of prescribing estrogen alone or with progestins might bear oncologic and thromboembolic risks and may even lead to litigation in case of a potentially related complication. However, it was known even before the WHI results that premature menopause and hypogonadism decreases the life expectancy of women by years through its skeletal and cardiovascular effects, and this negative effect correlates with the length of the hypoestrogenaemic period. Therefore, the denial of HRT also needs to be supported by evidence and should be weighed againts the risks of HRT. Yet, the oncologic risk of HRT is extremely difficult to assess. In this work we review the latest evidence from in vitro experiments to clinical studies, regarding HRT in survivors of gynecologic and non-gynecologic cancers. Based on our literature research, we group tumours regarding the oncologic risk of properly chosen female hormone replacement therapy in cancer survivors as follows: 'HRT is advanageous' (e.g. endometrial cancer type I, cervical adenocarcinoma, haematologic malignancies, local cutaneous malignant melanoma, colorectal cancer, hepatocellular cancer); 'HRT is neutral' (e.g. BRCA 1/2 mutation carriers without cancer, endometrial cancer type II, uterinal carcinosarcoma and adenosarcoma, certain types of ovarian cancer, cervical, vaginal and vulvar squamous cell carcinoma, prolactinoma, kidney cancer, pancreatic cancer, thyroid cancer); 'HRT is relatively contraindicated' for various reasons (e.g. leiomyosarcoma, certain types of ovarian tumours, brain tumours, advanced metastatic malignant melanoma, lung cancer, gastric cancer, bladder cancer); 'HRT is diasadvantageous and thus contraindicated' (e.g. breast cancer, endometrial stroma sarcoma, meningioma, glioma, hormone receptor positive gastric and bladder cancer).

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Section: Determinants Of Progesterone Effect On Tissuesmentioning

confidence: 99%

Section: Breast Cancermentioning

confidence: 99%

Hormone Replacement Therapy in Cancer Survivors – Review of the Literature

Deli

Orosz

Jakab

2019

Pathol. Oncol. Res.

135

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“…Progesterone itself shows classical actions via nuclear progesterone receptors (PRs) that, as a result of ligand binding, activate gene expression via progesterone response elements, as well as actions via nonclassical signalling pathways. Nonclassical actions are generally rapid and include activation of membrane‐bound PR, cytoplasmic PR or receptor‐independent intracellular signalling cascades . Allopregnanolone is produced from progesterone by the succeeding actions of the enzymes 5α‐reductase type I and 3α‐hydroxysteroid dehydrogenase.…”

Section: Introductionmentioning

confidence: 99%

“…Nonclassical actions are generally rapid and include activation of membrane-bound PR, cytoplasmic PR or receptor-independent intracellular signalling cascades. 2 Allopregnanolone is produced from progesterone by the succeeding actions of the enzymes 5α-reductase type I and 3α-hydroxysteroid dehydrogenase. These two enzymes are not homogenously expressed in the brain, although they are highly expressed and colocalised in, for example, specific neurones in the cerebral cortex, hippocampus and amygdala.…”

Section: Introductionmentioning

confidence: 99%

Effects of GABA active steroids in the female brain with a focus on the premenstrual dysphoric disorder

Bixo

Johansson

Timby

et al. 2018

J Neuroendocrinology

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Premenstrual dysphoric disorder (PMDD) afflicts 3%-5% of women of childbearing age, and is characterised by recurrent negative mood symptoms (eg, irritability, depression, anxiety and emotional lability) during the luteal phase of the menstrual cycle. The aetiology of PMDD is unknown, although a temporal association with circulating ovarian steroids, in particular progesterone and its metabolite allopregnanolone, has been established during the luteal phase. Allopregnanolone is a positive modulator of the GABA A receptor: it is sedative in high concentrations but may precipitate paradoxical adverse effects on mood at levels corresponding to luteal phase concentrations in susceptible women.Saccadic eye velocity (SEV) is a measure of GABA A receptor sensitivity; in experimental studies of healthy women, i.v. allopregnanolone decreases SEV. Women with PMDD display an altered sensitivity to an i.v. injection of allopregnanolone compared to healthy controls in this model. In functional magnetic resonance imaging (fMRI) studies, women with PMDD react differently to emotional stimuli in contrast to controls. A consistent finding in PMDD patients is increased amygdala reactivity during the luteal phase. Postmortem studies in humans have revealed that allopregnanolone concentrations vary across different brain regions, although mean levels in the brain also reflect variations in peripheral serum concentrations. The amygdala processes emotions such as anxiety and aggression. This is interesting because allopregnanolone is detected at high concentrations within the region into which marked increases in blood flow are measured with fMRI following progesterone/allopregnanolone administration. Allopregnanolone effects are antagonised by its isomer isoallopregnanolone (UC1010), which significantly reduces negative mood symptoms in women with PMDD when administered s.c. in the premenstrual phase. This was shown in a randomised, placebo-controlled clinical trial in which the primary outcome was change in symptom scoring on the Daily Rating of Severity of Problems (DRSP): the treatment reduced negative mood scores (P < .005), as well as total DRSP scores (P < .01), compared to placebo in women with PMDD. In conclusion, the underlying studies of this review provide evidence that allopregnanolone is the provoking factor behind the negative mood symptoms in PMDD and that isoallopregnanolone could ameliorate the symptoms as a result of its ability to antagonise the allopregnanolone effect on the GABA A receptor. K E Y W O R D SGABA, neuroactive steroids, premenstrual dysphoric disorder

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“…The classical seven-transmembrane P4 receptors (mPRα/β/γ/δ) were identi ed as putative G proteincoupled receptors (GPCRs) [35] and P4-induced signal transduction is involved in the activation of mitogen-activated protein kinases (MAPKs), inhibition of cAMP production and mobilization of intracellular Ca 2+ ions [35,36]. In contrast, PGRMC1 is a single-pass transmembrane domain-containing protein [27] primarily localized in the endomembrane (endoplasmic reticulum, Golgi apparatus, and mitochondria ) [3,37].…”

Section: Introductionmentioning

confidence: 99%

Progesterone-induced Warburg Effect is Regulated by Cell-type-specific Interaction of Progesterone Receptor Membrane Component 1 and Hexokinases

Sabbir¹,

Taylor²,

Zahradka³

2020

Preprint

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Background: Progesterone receptor membrane component 1 (PGRMC1) is a non-canonical progesterone (P4) binding protein. PGRMC1 is elevated in a variety of cancers and its phosphorylation state associated with hormone responsiveness in breast cancer. Metabolic reprogramming is a key factor for tumor growth during malignancies. Recently, we reported that the P4-inducedWarburg effectinHEK293cells is associated with altered post-translational modifications (PTMs) of PGRMC1, including phosphorylation, SUMOylation, and ubiquitination, which were linked to rapid proteasomal degradation of the protein. The previous study also identified hexokinase (HK) as a potential novel interacting partner of PGRMC1. HKs catalyze the first essential step of glucose metabolism and directly couple glycolysis to mitochondrial respiration. Therefore, in the present study, P4’s effects on glycolysis and PTMs of PGRMC1 as well as its interaction with HKs were compared between HEK293 and HepG2 cells to unravel the signaling pathways that mediate cell-type-specific metabolic reprogramming.Methods: P4-induced glucose metabolism in wild-type and PGRMC1-deficient cells wasassessed using the Seahorse flux analyzer, while PTMs of PGRMC1/HKs and protein-protein interaction were studied using immunoprecipitation, isoelectric focussing, phosphomimetics, and mass spectrometry.Translocation of HKs to different subcellular organelles were studied using subcellular fractionation, and the cell-type-specific effect of PGRMC1-deficiency on endoplasmic reticulum (ER) and mitochondria; ultrastructure were examined by electron microscopy. Results:P4 treatment caused a rapid increase in glycolysis in HEK293 cells, whereas it decreased glycolysis in HepG2 cells. In addition, PGRMC1 was not degraded in HepG2 cells which is in contrast to HEK293 cells where rapid proteasomal degradation of PGRMC1 occurredfollowing P4 treatment. Besides, PGRMC1 half-life and PTMs under basal condition were found cell-type-specific and the P4-induced PTMsdiffered between the two cell types. Furthermore, we observed cell-type-specific interaction of HKs with PGRMC1, and differential translocation of HK1/2 to the ER, mitochondria and nuclear compartments following P4 treatment. PGRMC1 deficiency altered ER structure in HepG2 cells. Thus, multiple factors underlying the cell-type-specific P4-PGRMC1-mediated metabolic reprogrammingwere identified. Conclusions: These findings provide a hitherto unknown novel P4-induced cell-type-specific PGRMC1-HK signaling mechanism that contributes to the molecular basis of P4-induced metabolic reprogramming, with important applications for hormone responsiveness in cancer.

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Progesterone-Mediated Non-Classical Signaling

Cited by 106 publications

References 93 publications

Hormone Replacement Therapy in Cancer Survivors – Review of the Literature

Hormone Replacement Therapy in Cancer Survivors – Review of the Literature

Effects of GABA active steroids in the female brain with a focus on the premenstrual dysphoric disorder

Progesterone-induced Warburg Effect is Regulated by Cell-type-specific Interaction of Progesterone Receptor Membrane Component 1 and Hexokinases

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