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Progesterone Receptor Membrane Component 1 Regulates Cellular Stress Responses and Inflammatory Pathways in Chronic Neuroinflammatory Conditions.

ABSTRACT: Alzheimer's disease (AD) is the leading cause of dementia and is one of the neurodegenerative diseases that are caused by neuronal death due to various triggers. Neuroinflammation plays a critical role in the development of AD. The neuroinflammatory response is manifested by pro-inflammatory cytokines, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-α; various chemokines; nitrous oxide; and reactive oxygen species. In this study, we evaluated the relevance of progesterone receptor membrane component 1 (PGRMC1), which is expressed in the brain cells during the induction of neuroinflammation. A lipopolysaccharide (LPS)-induced chronic neuroinflammation model and Pgrmc1 knockdown cells were used to assess the inflammatory cytokine levels, AD-related factors, inflammation-related signaling, and cell death. Pgrmc1 knockout (KO) mice had higher IL-1β levels after treatment with LPS compared with those of wild-type (WT) mice. Furthermore, Pgrmc1 KO mice had higher levels of inflammatory factors, endoplasmic reticulum stress indicators, and AD-associated markers compared with those of WT mice who underwent LPS treatment or not. Finally, these indicators were observed in vitro using U373-MG astrocytes. In conclusion, the loss of PGRMC1 may promote neuroinflammation and lead to AD.

SUBMITTER: Jo SL

PROVIDER: S-EPMC10886208 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Progesterone Receptor Membrane Component 1 Regulates Cellular Stress Responses and Inflammatory Pathways in Chronic Neuroinflammatory Conditions.

Jo Seong-Lae SL Hong Eui-Ju EJ

Antioxidants (Basel, Switzerland) 20240213 2

Alzheimer's disease (AD) is the leading cause of dementia and is one of the neurodegenerative diseases that are caused by neuronal death due to various triggers. Neuroinflammation plays a critical role in the development of AD. The neuroinflammatory response is manifested by pro-inflammatory cytokines, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-α; various chemokines; nitrous oxide; and reactive oxygen species. In this study, we evaluated the relevance of progesterone receptor m ...[more]

PMID: 38397828

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Project description:BackgroundPGRMC1 (progesterone receptor membrane component 1) is a highly conserved heme binding protein, which is overexpressed especially in hormone receptor-positive breast cancer and plays an important role in breast carcinogenesis. Nevertheless, little is known about the mechanisms by which PGRMC1 drives tumor progression. The aim of our study was to investigate the involvement of PGRMC1 in cholesterol metabolism to detect new mechanisms by which PGRMC1 can increase lipid metabolism and alter cancer-related signaling pathways leading to breast cancer progression.MethodsThe effect of PGRMC1 overexpression and silencing on cellular proliferation was examined in vitro and in a xenograft mouse model. Next, we investigated the interaction of PGRMC1 with enzymes involved in the cholesterol synthesis pathway such as CYP51, FDFT1, and SCD1. Further, the impact of PGRMC1 expression on lipid levels and expression of enzymes involved in lipid homeostasis was examined. Additionally, we assessed the role of PGRMC1 in key cancer-related signaling pathways including EGFR/HER2 and ERα signaling.ResultsOverexpression of PGRMC1 resulted in significantly enhanced proliferation. PGRMC1 interacted with key enzymes of the cholesterol synthesis pathway, alters the expression of proteins, and results in increased lipid levels. PGRMC1 also influenced lipid raft formation leading to altered expression of growth receptors in membranes of breast cancer cells. Analysis of activation of proteins revealed facilitated ERα and EGFR activation and downstream signaling dependent on PGRMC1 overexpression in hormone receptor-positive breast cancer cells. Depletion of cholesterol and fatty acids induced by statins reversed this growth benefit.ConclusionPGRMC1 may mediate proliferation and progression of breast cancer cells potentially by altering lipid metabolism and by activating key oncogenic signaling pathways, such as ERα expression and activation, as well as EGFR signaling. Our present study underlines the potential of PGRMC1 as a target for anti-cancer therapy.

Project description:BackgroundDecidualization of endometrial cells is the prerequisite for embryo implantation and subsequent placenta formation and is induced by rising progesterone levels following ovulation. One of the hormone receptors contributing to endometrial homeostasis is Progesterone Receptor Membrane Component 1 (PGRMC1), a non-classical membrane-bound progesterone receptor with yet unclear function. In this study, we aimed to investigate how PGRMC1 contributes to human decidualization.MethodsWe first analyzed PGRMC1 expression profile during a regular menstrual cycle in RNA-sequencing datasets. To further explore the function of PGRMC1 in human decidualization, we implemented an inducible decidualization system, which is achieved by culturing two human endometrial stromal cell lines in decidualization-inducing medium containing medroxyprogesterone acetate and 8-Br-cAMP. In our system, we measured PGRMC1 expression during hormone induction as well as decidualization status upon PGRMC1 knockdown at different time points. We further conferred proximity ligation assay to identify PGRMC1 interaction partners.ResultsIn a regular menstrual cycle, PGRMC1 mRNA expression is gradually decreased from the proliferative phase to the secretory phase. In in vitro experiments, we observed that PGRMC1 expression follows a rise-to-decline pattern, in which its expression level initially increased during the first 6 days after induction (PGRMC1 increasing phase) and decreased in the following days (PGRMC1 decreasing phase). Knockdown of PGRMC1 expression before the induction led to a failed decidualization, while its knockdown after induction did not inhibit decidualization, suggesting that the progestin-induced 'PGRMC1 increasing phase' is essential for normal decidualization. Furthermore, we found that the interactions of prohibitin 1 and prohibitin 2 with PGRMC1 were induced upon progestin treatment. Knocking down each of the prohibitins slowed down the decidualization process compared to the control, suggesting that PGRMC1 cooperates with prohibitins to regulate decidualization.ConclusionsAccording to our findings, PGRMC1 expression followed a progestin-induced rise-to-decline expression pattern during human endometrial decidualization process; and the correct execution of this expression program was crucial for successful decidualization. Thereby, the results of our in vitro model explained how PGRMC1 dysregulation during decidualization may present a new perspective on infertility-related diseases.

Dataset Information

Progesterone Receptor Membrane Component 1 Regulates Cellular Stress Responses and Inflammatory Pathways in Chronic Neuroinflammatory Conditions.

Publications

Progesterone Receptor Membrane Component 1 Regulates Cellular Stress Responses and Inflammatory Pathways in Chronic Neuroinflammatory Conditions.

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