The emerging role of progesterone receptor membrane component 1 (PGRMC1) in cancer biology

doi:10.1016/j.bbcan.2016.07.004

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

Volume 1866, Issue 2, December 2016, Pages 339-349

https://doi.org/10.1016/j.bbcan.2016.07.004 Get rights and content

Highlights

•
PGRMC1 is a putative progesterone receptor with many reported cellular functions.
•
A recently published crystal structure of PGRMC1 has revealed significant new insights into the function of this protein.
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PGMRC1 is emerging as a potential player in cancer development, progression and response to chemotherapy.

Abstract

Progesterone receptor membrane component 1 (PGRMC1) is a multi-functional protein with a heme-binding moiety related to that of cytochrome b₅, which is a putative progesterone receptor. The recently solved PGRMC1 structure revealed that heme-binding involves coordination by a tyrosinate ion at Y113, and induces dimerization which is stabilized by hydrophobic stacking of heme on adjacent monomers. Dimerization is required for association with cytochrome P450 (cyP450) enzymes, which mediates chemoresistance to doxorubicin and may be responsible for PGRMC1's anti-apoptotic activity. Here we review the multiple attested involvement of PGRMC1 in diverse functions, including regulation of cytochrome P450, steroidogenesis, vesicle trafficking, progesterone signaling and mitotic spindle and cell cycle regulation. Its wide range of biological functions is attested to particularly by its emerging association with cancer and progesterone-responsive female reproductive tissues. PGRMC1 exhibits all the hallmarks of a higher order nexus signal integration hub protein. It appears capable of acting as a detector that integrates information from kinase/phosphatase pathways with heme and CO levels and probably redox status.

Section snippets

Prelude

This review covers some of the best attested functions for PGRMC1 including heme-binding, cytochrome P450 interactions, steroidogenesis, membrane trafficking, and its putative roles as both a progesterone (P4) receptor and a component of the Sigma 2 receptor (S2R) complex. In addition, we place particular emphasis on functions of PGMRC1 that could affect the development of cancer. Insights gained into PGRMC1 function from its recently published structure are extended to consider regulation of

PGRMC1: Heme-binding, cytochrome P450 interactions and steroidogenesis

One of the earliest accepted PGRMC1 functions was related to heme-binding, which resides within its cytb5 domain that is situated on the cytoplasmic side of the endoplasmic reticulum (ER) membrane in the membrane-spanning PGRMC1 protein [1] (Fig. 1). Heme-binding is thought to be conserved among all members of the MAPR family [7].

Notably, cytb₅ itself interacts with cytochrome P450 (CyP450) enzymes, where the iron atom chelated to its heme moiety donates electrons to CyP450-mediated redox

PGRMC1 as a putative progesterone receptor

PGRMC1 has often been associated with P4-dependent effects, such as: (1) antagonizing estrogen-dependent effects in neurites in a P4-dependent manner [53], [54], [55]; (2) imposing a P4-dependent anti-apoptotic signal in spontaneously immortalized granulosa cells (SIGCs) [56], [57], [58], [59] or neurons [17]; and (3) mediating P4-dependent protective effects against cisplatin, doxorubicin and camptothecin in various cell-types [33], [60] (reviewed in [21]). In developing Purkinje cells of the

PGRMC1 and membrane trafficking

Runko et al., cloned rat PGRMC1 as a ventral midline antigen (which they called VEMA) that was involved in axon guidance in the developing rat central neural system [83]. They later showed that the Caenorhabditis elegans homologue to PGRMC1, which they called Vem-1, played a conserved role in nematode embryological axon guidance, where VEM-1 interacted with a cell surface protein related to the mammalian netrin receptors deleted in colorectal cancer (DCC) and neogenin [84]. In the latter paper,

PGRMC1 and progesterone responses revisited

From an analysis of the results described above in Section 5, the initially speculative prediction by Runko and Kaprielian [84] that PGRMC1 could be involved in membrane trafficking has been confirmed. Ironically, this may have implications for the status of PGRMC1 as a P4 receptor. Just as PGRMC1 could be responsible for the surface trafficking of vesicles containing netrin receptors, EGFR, GLP1-R, Aβ 42 oligomers, etc. (see Section 5 above), so it could also be responsible for the cell

PGRMC1 and cancer

Compelling evidence exists that PGRMC1 contributes to cancer pathology. Its abundance is up-regulated as reported for protein or mRNA data from a variety of tumors including lung, thyroid, colon, and tissues of the female reproductive system such as ovary, cervix and breast [2], [3], [21], [102], [103], [104], [105]. PGRMC1 regulates autophagy [106] implying altered metabolism, which is a cancer hallmark, as well as influencing cancer-relevant phenotypes such as: (1) the EMT; (2) resistance to

PGRMC1 and the sigma-2 receptor

The sigma-2 receptor (S2R) is an uncharacterized S2R ligand-binding activity (reviewed by [124]). S2R ligands preferentially kill dividing cancer cells by unknown mechanisms. The presence of S2R correlates with dividing cancer cells, as well as with various pathological conditions in the nervous system [125], [126], and can be used as a vehicle to specifically target anti-cancer drugs to tumor cells, including triple-negative breast [127], [128], ovarian [127], [129], and pancreatic [130]

Further insights from the PGRMC1 structure

The recent resolution of the PGRMC1's structure [25] reaffirmed some predictions that were made by modeling the PGRMC1 MAPR domain against related MAPR proteins [1], [8], [21], but has also led to exciting new insights. Heme-bound PGRMC1 exists as a disulfide-linked dimer, and dimerization is required for interaction with CyP450 enzymes. We can now rationalize previous reports that PGRMC1 exists sometimes in an apparent 54 kDa form that is susceptible to reducing agents (reviewed in [1]), and

Summary: PGRMC1 as a nexus hub protein

If the above discourse has compellingly demonstrated roles for PGRMC1 in CyP450-mediated enzyme reactions, steroidogenesis, lipogenesis, membrane trafficking, and potentially S2R activity, it is of interest to discuss that the spheres of PGRMC1 influence extend yet further. SUMOylation is associated with nuclear import [137], and SUMOYlated PGRMC1 is located within the nucleus, where it binds to transcription factors to affect gene activity itself [56]. The Human Protein Atlas [138] describes

Author contributions

MAC wrote the initial draft and made the figures. MAC and SC contributed the discussion of PGRMC1 in neural systems. All authors contributed to improving and editing the content of the manuscript.

Competing financial interests

MAC and SC are shareholders of Cognition Therapeutics Inc., who hold patents on S2R ligands for the treatment of disease conditions.

Transparency document

Transparency document.

Acknowledgments

This work was supported by Charles Sturt University (CSU) School of Biomedical Sciences (SBMS) Compact grant A541-900-xxx-40513 to M.A.C and J.A.J, SBMS support A534-900-xxx-41066 to M.A.C, and CSU Competitive grant A102-900-xxx-40002 to M.A.C. This work was also supported by a National Health and Medical Research Council Australia (NHMRC) Senior Principal Research Fellowship to D.R.R. (APP1062607), as well as NHMRC Peter Doherty Early Career Fellowship (APP1037323) and Cancer Institute NSW

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Estradiol and progesterone are key regulators of the menstrual cycle. In the human endometrium, progesterone induces morphological changes required for blastocyst implantation. Dysregulated response to progesterone can lead to endometrial pathologies including uterine bleeding and endometriosis. Besides the canonical nuclear progesterone receptor (encoded by the PGR gene), alternative response pathways include Progesterone Receptor Membrane Component 1 (PGRMC1), suspected to be involved in pathogenesis of endometrial diseases. We previously reported the spatiotemporal profile of PGRMC1 expression in the human endometrium along the menstrual cycle, highlighting progressive increase and decrease during the proliferative and secretory phases, respectively. Here we directly addressed its regulation by estradiol and progesterone, with systematic comparison with regulation of PGR expression. We found a direct correlation between expression of both genes during the proliferative and secretory phases in the cycling endometrium, but not during the menstrual phase. In a xenograft model mimicking the cycle phases, estradiol significantly increased and progesterone significantly decreased PGR expression but changes were not significant for PGRMC1. Finally, we did not find any significant effect of the ovarian steroids on expression of PGR or PGRMC1 in primary culture of endometrial stromal cells, except for a small increase in PGR expression by estradiol. Altogether, our experiments do not allow a major advance in our understanding of the mechanisms of cyclic variation of PGRMC1 expression, in particular regarding potential regulation by the ovarian steroids.
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Detrimental dietary habits with high-fat food are common in the psychiatric population, leading to higher obesity rate. Olanzapine (OLZ), as one of the mainstream antipsychotic drugs, shows superior efficacy in treating schizophrenia but limited by adverse effects such as obesity, dyslipidemia and liver injury, which are risk factors for the development of nonalcoholic fatty liver disease (NAFLD). Progesterone receptor component 1 (PGRMC1) is a key regulator associated with antipsychotic drug-induced metabolic disorders. Our study aims to investigate whether high-fat supplementation worsens OLZ-induced NAFLD and to validate the potential role of PGRMC1 pathway. In vivo, eight-week OLZ treatment successfully induced hepatic steatosis in female C57BL/6 mice fed with either a high-fat or normal diet, which is independent of body weight gain. Likewise, in vitro, OLZ markedly led to hepatocyte steatosis along with enhanced oxidative stress, which was aggravated by free fatty acids. Moreover, in vivo and in vitro, high-fat supplementation aggravated OLZ-induced hepatic lipid accumulation and oxidative stress via inhibition of hepatic PGRMC1-AMPK-mTORC1/Nrf2 pathways. Inspiringly, PGRMC1 overexpression effectively reversed OLZ-induced hepatocyte steatosis in vitro. Hence, hepatic PGRMC1 is attributable to OLZ-induced NAFLD especially with high-fat supplementation and potentially serves as a novel therapeutic target.
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Citation Excerpt :
When a protein is so highly expressed, regulation of expression may not be employed, but rather post-translational mechanisms may be used. Phosphorylation of PGRMC1 has been reported in cancer (Cahill et al., 2016; Neubauer et al., 2008). How PGRMC1 protein expression and function are regulated is an interesting area for future research.
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.
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The endometrium plays a crucial role in reproduction and, in humans, is cyclically remodeled under hormonal control. Estradiol favors tissue proliferation whereas progesterone inhibits tissue growth and induces morphological changes. Endometriosis is often associated with fertility issues and with exacerbated estrogen and reduced progesterone concentration or response in the eutopic endometrium. However, underlying mechanisms remain unclear. Progesterone Receptor Membrane Component (PGRMC) 1 is a protein able to modulate progesterone response and its murine knockout reduced fertility. However, the precise spatiotemporal pattern of PGRMC1 expression in the human endometrium is still poorly characterized. We investigated variations of eutopic endometrial PGRMC1 expression by combining RT-qPCR, immunofluorescence and in situ hybridization. We found that PGRMC1 expression progressively increases during the proliferative phase and decreases during the secretory phase. However, immunolabeling and identification of mRNA-containing cells were regularly heterogeneous in samples, according to tissue depth, with a gradient extending from the surface epithelium towards the basalis. There was no significant difference in PGRMC1 mRNA amounts between patients with or without endometriosis or adenomyosis, for any phase of the menstrual cycle, but cells with strong or moderate PGRMC1 immunolabeling were reduced during the proliferative phase in endometriotic patients. In conclusion, although the cyclical variation of PGRMC1 expression globally follows fluctuation of ovarian steroids, further work is required to precisely characterize hormonal control and identify the additional levels of regulation responsible for local adjustment of PGRMC1 concentration. This is particularly important in the light of recent studies emphasizing the correlation between adequate PGRMC1 amounts and fertility.
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ReviewThe emerging role of progesterone receptor membrane component 1 (PGRMC1) in cancer biology

Highlights

Abstract

Section snippets

Prelude

PGRMC1: Heme-binding, cytochrome P450 interactions and steroidogenesis

PGRMC1 as a putative progesterone receptor

PGRMC1 and membrane trafficking

PGRMC1 and progesterone responses revisited

PGRMC1 and cancer

PGRMC1 and the sigma-2 receptor

Further insights from the PGRMC1 structure

Summary: PGRMC1 as a nexus hub protein

Author contributions

Competing financial interests

Transparency document

Acknowledgments

J. Steroid Biochem. Mol. Biol.

Steroids

J. Biol. Chem.

Mol. Cell. Proteomics

J. Steroid Biochem. Mol. Biol.

J. Thromb. Haemost.

Pharmacol. Ther.

Cell Metab.

Cancer Lett.

J. Pharm. Biomed. Anal.

J. Proteome

Mol. Cell. Endocrinol.

Cell Metab.

Cancer Cell

Cancer Cell

Mol. Cell. Endocrinol.

Genomics

Neuroscience

Taiwan J. Obstet. Gynecol.

Reprod. BioMed. Online

Fertil. Steril.

Biochim. Biophys. Acta

Mol. Cell. Proteomics

Mol. Cell. Neurosci.

Mol. Cell. Proteomics

J. Biol. Chem.

Neuron

Neuron

Neuron

S2R(Pgrmc1): the cytochrome-related sigma-2 receptor that regulates lipid and drug metabolism and hormone signaling

Expert Opin. Drug Metab. Toxicol.

Isolation and characterization of a novel gene induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin in rat liver

Carcinogenesis

Purification and partial sequencing of high-affinity progesterone-binding site(s) from porcine liver membranes

Eur. J. Biochem.

Cloning and tissue expression of two putative steroid membrane receptors

Biol. Chem.

Functions of MAPR (membrane-associated progesterone receptor) family members as heme/steroid-binding proteins

Curr. Protein Pept. Sci.

Membrane-bound progesterone receptors contain a cytochrome b5-like ligand-binding domain

Genome Biol.

A structure-based strategy for discovery of small ligands binding to functionally unknown proteins: combination of in silico screening and surface plasmon resonance measurements

Proteomics

Progesterone receptor membrane component 1 (Pgrmc1): a heme-1 domain protein that promotes tumorigenesis and is inhibited by a small molecule

J. Pharmacol. Exp. Ther.

Progesterone directly and rapidly inhibits GnRH neuronal activity via progesterone receptor membrane component 1

Endocrinology

Elevated progesterone receptor membrane component 1/sigma-2 receptor levels in lung tumors and plasma from lung cancer patients

Int. J. Cancer

Progesterone receptor signalling in retinal photoreceptor neuroprotection

J. Neurochem.

Antagonistic effect of a salivary proline-rich peptide on the cytosolic Ca2 + mobilization induced by progesterone in oral squamous cancer cells

PLoS One

Role of Pgrmc1 in estrogen maintenance of meiotic arrest in zebrafish oocytes through Gper/Egfr

J. Endocrinol.

New aspects of progesterone interactions with the actin cytoskeleton and neurosteroidogenesis in the cerebellum and the neuronal growth cone

J. Histochem. Cytochem.

Progesterone receptor membrane component 1 modulates human cytochrome p450 activities in an isoform-dependent manner

Drug Metab. Dispos.

Progesterone receptor membrane component 1 inhibits the activity of drug-metabolizing cytochromes P450 and binds to cytochrome P450 reductase

Mol. Pharmacol.

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

Nat. Commun.

Review
The emerging role of progesterone receptor membrane component 1 (PGRMC1) in cancer biology