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PGRMC1 Promotes Progestin-Dependent Proliferation of Breast Cancer Cells by Binding Prohibitins Resulting in Activation of ERα Signaling.

ABSTRACT: In previous studies, we reported that progesterone receptor membrane component 1 (PGRMC1) is implicated in progestin signaling and possibly associated with increased breast cancer risk upon combined hormone replacement therapy. To gain mechanistic insight, we searched for potential PGRMC1 interaction partners upon progestin treatment by co-immunoprecipitation and mass spectrometry. The interactions with the identified partners were further characterized with respect to PGRMC1 phosphorylation status and with emphasis on the crosstalk between PGRMC1 and estrogen receptor α (ERα). We report that PGRMC1 overexpression resulted in increased proliferation of hormone receptor positive breast cancer cell lines upon treatment with a subgroup of progestins including norethisterone and dydrogesterone that promote PGRMC1-phosphorylation on S181. The ERα modulators prohibitin-1 (PHB1) and prohibitin-2 (PHB2) interact with PGRMC1 in dependency on S181-phosphorylation upon treatment with the same progestins. Moreover, increased interaction between PGRMC1 and PHBs correlated with decreased binding of PHBs to ERα and subsequent ERα activation. Inhibition of either PGRMC1 or ERα abolished this effect. In summary, we provide strong evidence that activated PGRMC1 associates with PHBs, competitively removing them from ERα, which then can develop its transcriptional activities on target genes. This study emphasizes the role of PGRMC1 in a key breast cancer signaling pathway which may provide a new avenue to target hormone-dependent breast cancer.

SUBMITTER: Bai Y

PROVIDER: S-EPMC8615993 | biostudies-literature |

REPOSITORIES: biostudies-literature

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PGRMC1 promotes progestin-dependent proliferation of breast cancer cells by binding prohibitins resulting in activation of ERα signaling

Project description:Combined menopausal hormone therapy is associated with increased breast cancer risk in postmenopausal women. In our previous studies, progesterone receptor membrane component 1 (PGRMC1) was shown to play a role in progestins’ mode of action, resulting in enhanced proliferation of breast cancer cells. Here we describe a potential mechanism by which PGRMC1 contributes to breast cancer progression via interaction with prohibitins, inhibiting their function as transcription factor repressors, thereby facilitating estrogen receptor alpha (ERα) transcriptional activity and enhancing oncogenic signaling upon treatment with certain progestins, such as norethisterone and dydrogesterone.

2022-02-16 | PXD028537 | Pride

PGRMC1-dependent lipophagy promotes ferroptosis in paclitaxel-tolerant persister cancer cells.

Project description:BackgroundProgesterone receptor membrane component 1 (PGRMC1) is a heme-binding protein inducing dimerization with cytochrome P450, which mediates chemoresistance. Increased PGRMC1 expression is found in multiple types of resistant cancers, but the role of PGRMC1 in the ferroptosis of cancer cells remains unrevealed. Therefore, we examined the role of PGRMC1 in promoting ferroptosis in paclitaxel-tolerant persister cancer cells (PCC).MethodsThe effects of ferroptosis inducers and PGRMC1 gene silencing/overexpression were tested on head and neck cancer (HNC) cell lines and mouse tumor xenograft models. The results were analyzed about cell viability, death, lipid ROS and iron production, mRNA/protein expression and interaction, and lipid assays.ResultsPCC had more free fatty acids, lipid droplets, and fatty acid oxidation (FAO) than their parental cells. PCC was highly sensitive to inhibitors of system xc- cystine/glutamate antiporter (xCT), such as erastin, sulfasalazine, and cyst(e)ine deprivation, but less sensitive to (1S,3R)-RSL3. PGRMC1 silencing in PCC reduced ferroptosis sensitivity by xCT inhibitors, and PGRMC1 overexpression in parental cells increased ferroptosis by xCT inhibitors. Lipid droplets were degraded along with autophagy induction and autophagosome formation by erastin treatment in PCC. Lipophagy was accompanied by increased tubulin detyrosination, which was increased by SIRT1 activation but decreased by SIRT1 inhibition. FAO and lipophagy were also promoted by the interaction between lipid droplets and mitochondria.ConclusionPGRMC1 expression increased FAO and ferroptosis sensitivity from in vivo mice experiments. Our data suggest that PGRMC1 promotes ferroptosis by xCT inhibition in PCC.

| S-EPMC8573965 | biostudies-literature

Haem-dependent dimerization of PGRMC1/Sigma-2 receptor facilitates cancer proliferation and chemoresistance.

Project description:Progesterone-receptor membrane component 1 (PGRMC1/Sigma-2 receptor) is a haem-containing protein that interacts with epidermal growth factor receptor (EGFR) and cytochromes P450 to regulate cancer proliferation and chemoresistance; its structural basis remains unknown. Here crystallographic analyses of the PGRMC1 cytosolic domain at 1.95 Å resolution reveal that it forms a stable dimer through stacking interactions of two protruding haem molecules. The haem iron is five-coordinated by Tyr113, and the open surface of the haem mediates dimerization. Carbon monoxide (CO) interferes with PGRMC1 dimerization by binding to the sixth coordination site of the haem. Haem-mediated PGRMC1 dimerization is required for interactions with EGFR and cytochromes P450, cancer proliferation and chemoresistance against anti-cancer drugs; these events are attenuated by either CO or haem deprivation in cancer cells. This study demonstrates protein dimerization via haem-haem stacking, which has not been seen in eukaryotes, and provides insights into its functional significance in cancer.

| S-EPMC4802085 | biostudies-literature

Prohibitins are required for cancer cell proliferation and adhesion.

Project description:Prohibitin 1 (PHB1) is a highly conserved protein that together with its homologue prohibitin 2 (PHB2) mainly localizes to the inner mitochondrial membrane. Although it was originally identified by its ability to inhibit G1/S progression in human fibroblasts, its role as tumor suppressor is debated. To determine the function of prohibitins in maintaining cell homeostasis, we generated cancer cell lines expressing prohibitin-directed shRNAs. We show that prohibitin proteins are necessary for the proliferation of cancer cells. Down-regulation of prohibitin expression drastically reduced the rate of cell division. Furthermore, mitochondrial morphology was not affected, but loss of prohibitins did lead to the degradation of the fusion protein OPA1 and, in certain cancer cell lines, to a reduced capability to exhibit anchorage-independent growth. These cancer cells also exhibited reduced adhesion to the extracellular matrix. Taken together, these observations suggest prohibitins play a crucial role in adhesion processes in the cell and thereby sustaining cancer cell propagation and survival.

| S-EPMC2939069 | biostudies-literature

Promoter-proximal CTCF binding promotes distal enhancer-dependent gene activation.

Project description:The CCCTC-binding factor (CTCF) works together with the cohesin complex to drive the formation of chromatin loops and topologically associating domains, but its role in gene regulation has not been fully defined. Here, we investigated the effects of acute CTCF loss on chromatin architecture and transcriptional programs in mouse embryonic stem cells undergoing differentiation to neural precursor cells. We identified CTCF-dependent enhancer-promoter contacts genome-wide and found that they disproportionately affect genes that are bound by CTCF at the promoter and are dependent on long-distance enhancers. Disruption of promoter-proximal CTCF binding reduced both long-range enhancer-promoter contacts and transcription, which were restored by artificial tethering of CTCF to the promoter. Promoter-proximal CTCF binding is correlated with the transcription of over 2,000 genes across a diverse set of adult tissues. Taken together, the results of our study show that CTCF binding to promoters may promote long-distance enhancer-dependent transcription at specific genes in diverse cell types.

| S-EPMC7913465 | biostudies-literature

PGRMC1: An enigmatic heme-binding protein.

Project description:Progesterone Receptor Membrane Component 1 (PGRMC1) is a heme-binding protein that has been implicated in a wide range of cell and tissue functions, including cytochromes P450 activity, heme homeostasis, cancer, female reproduction, and protein quality control. Despite an extensive body of literature, a relative lack of mechanistic insight means that how PGRMC1 functions in these different aspects of biology is largely unknown. This review provides an overview of the PGRMC1 literature, highlighting what information is rigorously supported by experimental evidence and where additional investigation is warranted. The central role of PGRMC1 in supporting cytochrome P450 activity is discussed at length. Building on existing models of PGRMC1 function, a speculative model is proposed using the reviewed literature in which PGRMC1 functions as a heme chaperone to shuttle heme from its site of synthesis in the mitochondrion to other subcellular compartments. By spotlighting knowledge gaps, this review will motivate investigators to better understand this enigmatic protein.

| S-EPMC9839567 | biostudies-literature

Immune activation resulting from NKG2D/ligand interaction promotes atherosclerosis.

Project description:BackgroundThe interplay between the immune system and abnormal metabolic conditions sustains and propagates a vicious feedback cycle of chronic inflammation and metabolic dysfunction that is critical for atherosclerotic progression. It is well established that abnormal metabolic conditions, such as dyslipidemia and hyperglycemia, cause various cellular stress responses that induce tissue inflammation and immune cell activation, which in turn exacerbate the metabolic dysfunction. However, molecular events linking these processes are not well understood.Methods and resultsTissues and organs of humans and mice with hyperglycemia and hyperlipidemia were examined for expression of ligands for NKG2D, a potent immune-activating receptor expressed by several types of immune cells, and the role of NKG2D in atherosclerosis and metabolic diseases was probed with the use of mice lacking NKG2D or by blocking NKG2D with monoclonal antibodies. NKG2D ligands were upregulated in multiple organs, particularly atherosclerotic aortas and inflamed livers. Ligand upregulation was induced in vitro by abnormal metabolites associated with metabolic dysfunctions. Using apolipoprotein E-deficient mouse models, we demonstrated that preventing NKG2D functions resulted in a dramatic reduction in plaque formation, suppressed systemic and organ inflammation mediated by multiple immune cell types, and alleviated abnormal metabolic conditions.ConclusionsThe NKG2D/ligand interaction is a critical molecular link in the vicious cycle of chronic inflammation and metabolic dysfunction that promotes atherosclerosis and might be a useful target for therapeutic intervention in the disease.

| S-EPMC3289255 | biostudies-literature

Elevated MiR-222-3p promotes proliferation and invasion of endometrial carcinoma via targeting ERα.

Project description:MicroRNAs play key roles in tumor proliferation and invasion. Here we show distinct expression of miR-222-3p between ERα-positive and ERα-negative endometrial carcinoma (EC) cell lines and primary tumors, and investigation of its relationship with ERα and other clinical parameters. In vitro, the function of miR-222-3p was examined in RL95-2 and AN3CA cell lines. MiR-222-3p expression was negatively correlated with ERα. Over-expressed miR-222-3p in RL95-2 cells promoted cell proliferation, enhanced invasiveness and induced a G1 to S phase shift in cell cycle. Furthermore, the miR-222-3p inhibitor decreased the activity of AN3CA cells to proliferate and invade. In vivo, down-regulated miR-222-3p of AN3CA cells inhibited EC tumor growth in a mouse xenograft model. Additionally, miR-222-3p increased raloxifene resistance through suppressing ERα expression in EC cells. In conclusion, miR-222-3p plays a significant role in the regulation of ERα expression and could be potential targets for restoring ERα expression and responding to antiestrogen therapy in a subset of ECs.

| S-EPMC3909214 | biostudies-literature

A medical records based study for KLK8 promotes the proliferation and metastasis of colorectal cancer via the activation of EMT associated with PAR1

Project description:Interventions: Case series:No Primary outcome(s): KLK8 protein concentration Study Design: Single arm

| 2716952 | ecrin-mdr-crc

Super-enhancer-controlled positive feedback loop BRD4/ERα-RET-ERα promotes ERα-positive breast cancer.

Project description:Estrogen and estrogen receptor alpha (ERα)-induced gene transcription is tightly associated with ERα-positive breast carcinogenesis. ERα-occupied enhancers, particularly super-enhancers, have been suggested to play a vital role in regulating such transcriptional events. However, the landscape of ERα-occupied super-enhancers (ERSEs) as well as key ERα-induced target genes associated with ERSEs remain to be fully characterized. Here, we defined the landscape of ERSEs in ERα-positive breast cancer cell lines, and demonstrated that bromodomain protein BRD4 is a master regulator of the transcriptional activation of ERSEs and cognate ERα target genes. RET, a member of the tyrosine protein kinase family of proteins, was identified to be a key ERα target gene of BRD4-regulated ERSEs, which, in turn, is vital for ERα-induced gene transcriptional activation and malignant phenotypes through activating the RAS/RAF/MEK2/ERK/p90RSK/ERα phosphorylation cascade. Combination therapy with BRD4 and RET inhibitors exhibited additive effects on suppressing ERα-positive breast cancer both in vitro and in vivo, comparable with that of standard endocrine therapy tamoxifen. Furthermore, combination therapy re-sensitized a tamoxifen-resistant ERα-positive breast cancer cell line to tamoxifen treatment. Taken together, our data uncovered the critical role of a super-enhancer-associated positive feedback loop constituting BRD4/ERα-RET-ERα in ERα-positive breast cancer, and suggested that targeting components in this loop would provide a new therapeutic avenue for treating ERα-positive breast cancer in the clinic.

| S-EPMC9561272 | biostudies-literature

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