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Glucocorticoids Influencing Wnt/?-Catenin Pathway; Multiple Sites, Heterogeneous Effects.

ABSTRACT: Glucocorticoid hormones are vital; their accurate operation is a necessity at all ages and in all life situations. Glucocorticoids regulate diverse physiological processes and they use many signaling pathways to fulfill their effect. As the operation of these hormones affects many organs, the excess of glucocorticoids is actually detrimental to the whole human body. The endogenous glucocorticoid excess is a relatively rare condition, but a significant proportion of adult people uses glucocorticoid medication for the treatment of chronic illnesses, therefore they are exposed to the side effects of long-term glucocorticoid treatment. Our review summarizes the adverse effects of glucocorticoid excess affecting bones, adipose tissue, brain and skin, focusing on those effects which involve the Wnt/?-catenin pathway.

SUBMITTER: Meszaros K

PROVIDER: S-EPMC7181001 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Glucocorticoids Influencing Wnt/β-Catenin Pathway; Multiple Sites, Heterogeneous Effects.

Meszaros Katalin K Patocs Attila A

Molecules (Basel, Switzerland) 20200325 7

Glucocorticoid hormones are vital; their accurate operation is a necessity at all ages and in all life situations. Glucocorticoids regulate diverse physiological processes and they use many signaling pathways to fulfill their effect. As the operation of these hormones affects many organs, the excess of glucocorticoids is actually detrimental to the whole human body. The endogenous glucocorticoid excess is a relatively rare condition, but a significant proportion of adult people uses glucocortico ...[more]

PMID: 32218328

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Project description:BackgroundGlioblastoma and Alzheimer's disease (AD) are the most common and devastating diseases in the central nervous system. The dysfunction of Presenilin1 is the main reason for AD pathogenesis. However, the molecular function of Presenilin1 and its relative mechanism in glioblastoma remain unclear.MethodsExpression of presenilin1 in glioma was determined by IHC. CCK-8, colony formation, Flow cytometry, Edu staining were utilized to evaluate functions of presenilin1 on glioblastoma proliferation. The mechanism of above process was assessed by Western blotting and cell immunofluorescence. Mouse transplanting glioblastoma model and micro-MRI detection were used to verified presenilin1 function in vivo.ResultsIn this study, we found that all grades of glioma maintained relatively low Presenilin1 expression and that the expression of Presenilin1 in high-grade glioma was significantly lower than that in low-grade glioma. Moreover, the Presenilin1 level had a positive correlation with glioma and glioblastoma patient prognosis. Next, we determined that Presenilin1 inhibited the growth and proliferation of glioblastoma cells by downregulating CDK6, C-myc and Cyclin D1 to arrest the cell cycle at the G1/S phase. Mechanistically, Presenilin1 promoted the direct phosphorylation of ?-catenin at the 45 site and indirect phosphorylation at the 33/37/41 site, then decreased the stabilized part of ?-catenin and hindered its translocation from the cytoplasm to the nucleus. Furthermore, we found that Presenilin1 downregulation clearly accelerated the growth of subcutaneous glioblastoma, and Presenilin1 overexpression significantly repressed the subcutaneous and intracranial transplantation of glioblastoma by hindering ?-catenin-dependent cell proliferation.ConclusionOur data implicate the antiproliferative effect of Presenilin1 in glioblastoma by suppressing Wnt/?-catenin signaling, which may provide a novel therapeutic agent for glioblastoma. Video Abstract.

Project description:ContextThe shift in maternal energy metabolism characteristic of pregnancy is thought to be driven by various hormonal changes, especially of ovarian and placental steroids. Imbalances in circulating estradiol (E2) and progesterone (P4) levels during this period are often associated with metabolic disturbances leading to the development of gestational diabetes mellitus (GDM). Since abnormalities in the Wnt pathway effector transcription factor 7-like 2 (TCF7L2) are commonly associated with the occurrence of GDM, we hypothesized that the canonical or β-catenin-dependent Wnt signaling pathway mediates the metabolic actions of E2 and P4.ObjectiveOur study was aimed at elucidating the metabolic function of the steroids E2 and P4, and examining the role of the canonical Wnt signaling pathway in mediating the actions of these steroids.MethodsThe ovariectomized (OVX) rat was used as a model system to study the effect of known concentrations of exogenously administered E2 and P4. Niclosamide (Nic) was administered to block Wnt signaling. 3T3-L1 cells were used to analyze changes in differentiation in the presence of the steroids or niclosamide.ResultsIn the present study, we observed that E2 enhanced insulin sensitivity and inhibited lipogenesis while P4 increased lipogenic gene expression-in 3T3-L1 adipocytes, and in adipose tissue and skeletal muscle of OVX rats when the dosage of E2 and P4 mimicked that of pregnancy. Both E2 and P4 were also found to upregulate Wnt signaling. Nic nhibited the steroid-mediated increase in Wnt signaling in adipocytes and OVX rats. The insulin-sensitizing and antilipogenic actions of E2 were found to be mediated by the canonical Wnt pathway, but the effects of P4 on lipogenesis appeared to be independent of it. Additionally, it was observed that inhibition of Wnt signaling by Nic hastened adipogenic differentiation, and the inhibitory effect of E2 on differentiation was prevented by Nic.ConclusionThe findings presented in this study highlight the role of steroids and Wnt pathway in glucose and lipid metabolism and are relevant to understanding the pathophysiology of metabolic disorders arising from hormonal disturbances.

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Glucocorticoids Influencing Wnt/?-Catenin Pathway; Multiple Sites, Heterogeneous Effects.

Publications

Glucocorticoids Influencing Wnt/β-Catenin Pathway; Multiple Sites, Heterogeneous Effects.

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