Progesterone receptor membrane component 1 (PGRMC1)-mediated progesterone effect on preimplantation development of in vitro produced porcine embryos

Context: Progesterone (P4) promotes its own secretion and the survival of human granulosa/luteal (GL) cells. Objective: The objective of these studies was to determine whether progesterone receptor membrane component-1 (PGRMC1) mediates P4’s actions. Design: In vitro studies were conducted on GL cells from women undergoing in vitro fertilization and GL5 cells, which are derived from GL cells. Setting and Patients: GL cells were obtained from women undergoing fertility treatment at a university-based clinic and used for in vitro studies. Main Outcome Measures: PCR, Western blot, and immunocytochemistry were used to detect various progestin binding proteins. 3H-P4 binding kinetics were assessed on partially purified PGRMC1. Apoptosis was determined after culture by either TUNEL or DAPI staining. P4 was measured by an ELISA assay. PGRMC1 was depleted using small interfering RNA. Results: GL and GL5 cells expressed several P4 binding proteins including the nuclear progesterone receptor (PGR), progestin/adipoQ receptors (PAQR 7, 8, and 5) and PGRMC1. Ligand binding studies revealed that both P4 and the progestin, R5020, bound PGRMC1 with an EC50 of approximately 10 nm. Interestingly, P4 inhibited apoptosis at concentrations in the 10 nm range, whereas R5020 stimulated P4 secretion at concentrations of at lease 16 μm. Depleting PGRMC1 attenuated P4’s antiapoptotic action but failed to influence R5020-induced P4 secretion. Conclusions: These studies conclusively demonstrate that in human GL cells PGRMC1 functions as a receptor through which P4 activates a signal cascade that prevents apoptosis. In contrast, PGRMC1 does not mediate P4’s ability to acutely promote its own secretion.

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Progesterone receptor membrane component 1 expression and putative function in bovine oocyte maturation, fertilization, and early embryonic development

Reproduction ◽

10.1530/rep-10-0218 ◽

2010 ◽

Vol 140 (5) ◽

pp. 663-672 ◽

Cited By ~ 35

Author(s):

Alberto M Luciano ◽

Valentina Lodde ◽

Federica Franciosi ◽

Fabrizio Ceciliani ◽

John J Peluso

Keyword(s):

Progesterone Receptor ◽

Embryonic Development ◽

Oocyte Maturation ◽

Centromeric Region ◽

Confocal Imaging ◽

Membrane Component ◽

Aurora Kinase B ◽

Receptor Membrane ◽

Bovine Oocytes

Although the mRNA that encodes progesterone receptor membrane component 1 (PGRMC1) is present in mammalian oocytes, nothing is known about either PGRMC1's expression pattern or function in oocytes during maturation, fertilization, and subsequent embryonic development. As PGRMC1 associates with the mitotic spindle in somatic cells, we hypothesized that PGRMC1 is involved in oocyte maturation (meiosis). Western blot analysis confirmed the presence of PGRMC1 in bovine oocytes. This study also shows that PGRMC1 is present at the germinal vesicle (GV)- and MII-stage oocytes and is associated with male and female pronucleus formation of the zygote and is highly expressed in blastocysts. A more detailed examination of PGRMC1 localization using confocal imaging demonstrated that in GV-stage oocytes, PGRMC1 was concentrated throughout the GV but did not localize to the chromatin. With the resumption of meiosis in vitro, PGRMC1 concentrated in the centromeric region of metaphase I chromosomes, while in the anaphase I/telophase I stages the majority of PGRMC1 concentrated between the separating chromosomes. At the metaphase II stage, PGRMC1 re-associated with the centromeric region of the chromosomes. A colocalization study demonstrated that PGRMC1 associated with the phosphorylated form of aurora kinase B, which localizes to the centromeres at metaphase. Finally, PGRMC1 antibody injection significantly lowered the percentage of oocytes that matured and reached the metaphase II stage after 24 h of culture. The majority of the PGRMC1 antibody-injected oocytes arrested in the prometaphase I stage of meiosis. Furthermore, in most of the PGRMC1 antibody-injected oocytes, the chromosomes were disorganized and scattered. Taken together, these data demonstrate that PGRMC1 is expressed in bovine oocytes and its localization changes at specific stages of oocyte maturation. These observations suggest an important role for PGRMC1 in oocyte maturation, which may be specifically related to the mechanism by which chromosomes segregate.

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Progesterone Receptor Membrane Component 1 Promotes Endometrial and Breast Cancer Cell Viability in Response to Chemotherapy In Vitro and In Vivo.

Biology of Reproduction ◽

10.1093/biolreprod/81.s1.98 ◽

2009 ◽

Vol 81 (Suppl_1) ◽

pp. 98-98 ◽

Cited By ~ 2

Author(s):

James K. Pru ◽

Anne M. Friel ◽

Ling Zhang ◽

Leen J. Blok ◽

Toshi Shioda ◽

...

Keyword(s):

Breast Cancer ◽

Progesterone Receptor ◽

Cell Viability ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Membrane Component ◽

Receptor Membrane ◽

Response To Chemotherapy

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The relationship between follicle development and progesterone receptor membrane component-1 expression in women undergoing in vitro fertilization

Fertility and Sterility ◽

10.1016/j.fertnstert.2011.12.026 ◽

2012 ◽

Vol 97 (3) ◽

pp. 572-578 ◽

Cited By ~ 15

Author(s):

Alyaa Elassar ◽

Xiufang Liu ◽

Victoria Scranton ◽

Carol A. Wu ◽

John J. Peluso

Keyword(s):

In Vitro Fertilization ◽

Progesterone Receptor ◽

Follicle Development ◽

Membrane Component ◽

Vitro Fertilization ◽

Receptor Membrane ◽

The Relationship

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In vitro inhibition of SKOV-3 cell migration as a distinctive feature of progesterone receptor membrane component type 2 versus type 1

Steroids ◽

10.1016/j.steroids.2012.09.006 ◽

2012 ◽

Vol 77 (14) ◽

pp. 1543-1550 ◽

Cited By ~ 23

Author(s):

Christian Albrecht ◽

Volker Huck ◽

Martin Wehling ◽

Alexandra Wendler

Keyword(s):

Cell Migration ◽

Progesterone Receptor ◽

Distinctive Feature ◽

Membrane Component ◽

Receptor Membrane ◽

Component Type ◽

In Vitro Inhibition

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Progesterone Receptor Membrane Component 1 as the Mediator of the Inhibitory Effect of Progestins on Cytokine-Induced Matrix Metalloproteinase 9 Activity In Vitro

Reproductive Sciences ◽

10.1177/1933719113493514 ◽

2013 ◽

Vol 21 (2) ◽

pp. 260-268 ◽

Cited By ~ 20

Author(s):

Terrence K. Allen ◽

Liping Feng ◽

Chad A. Grotegut ◽

Amy P. Murtha

Keyword(s):

Progesterone Receptor ◽

Matrix Metalloproteinase ◽

Inhibitory Effect ◽

Matrix Metalloproteinase 9 ◽

Membrane Component ◽

Receptor Membrane ◽

Metalloproteinase 9

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Progesterone receptor membrane component-1 promotes cancer cell proliferation and resistance to anthracycline treatment in breast cancer

Senologie - Zeitschrift für Mammadiagnostik und -therapie ◽

10.1055/s-0037-1602575 ◽

2017 ◽

Vol 14 (02) ◽

pp. A1-A53

Author(s):

M Willibald ◽

I Wurster ◽

G Bayer ◽

H Seeger ◽

AO Mueck ◽

...

Keyword(s):

Breast Cancer ◽

Cell Proliferation ◽

Progesterone Receptor ◽

Cancer Cell ◽

Cancer Cell Proliferation ◽

Membrane Component ◽

Receptor Membrane

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Upon Progestin Stimulation Progesterone Receptor Membrane Component-1 is Phosphorylated in Breast Cancer Cells and Binds to Estrogen Receptor α-Coregulators PHB1 and PHB2

10.1055/s-0037-1606151 ◽

2017 ◽

Author(s):

M Willibald ◽

G Bayer ◽

V Stahlhut ◽

G Poschmann ◽

K Stühler ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Progesterone Receptor ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Estrogen Receptor Α ◽

Membrane Component ◽

Receptor Membrane

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Glycyrrhizin Derivatives Suppress Cancer Chemoresistance by Inhibiting Progesterone Receptor Membrane Component 1

Cancers ◽

10.3390/cancers13133265 ◽

2021 ◽

Vol 13 (13) ◽

pp. 3265

Author(s):

Yasuaki Kabe ◽

Ikko Koike ◽

Tatsuya Yamamoto ◽

Miwa Hirai ◽

Ayaka Kanai ◽

...

Keyword(s):

Progesterone Receptor ◽

Cancer Progression ◽

Egf Receptor ◽

Ldl Receptor ◽

Density Lipoprotein ◽

Human Colon ◽

Titration Calorimetry ◽

Membrane Component ◽

Human Colon Cancer ◽

Receptor Membrane

Progesterone receptor membrane component 1 (PGRMC1) is highly expressed in various cancer cells and contributes to tumor progression. We have previously shown that PGRMC1 forms a unique heme-stacking functional dimer to enhance EGF receptor (EGFR) activity required for cancer proliferation and chemoresistance, and the dimer dissociates by carbon monoxide to attenuate its biological actions. Here, we determined that glycyrrhizin (GL), which is conventionally used to ameliorate inflammation, specifically binds to heme-dimerized PGRMC1. Binding analyses using isothermal titration calorimetry revealed that some GL derivatives, including its glucoside-derivative (GlucoGL), bind to PGRMC1 potently, whereas its aglycone, glycyrrhetinic acid (GA), does not bind. GL and GlucoGL inhibit the interaction between PGRMC1 and EGFR, thereby suppressing EGFR-mediated signaling required for cancer progression. GL and GlucoGL significantly enhanced EGFR inhibitor erlotinib- or cisplatin (CDDP)-induced cell death in human colon cancer HCT116 cells. In addition, GL derivatives suppressed the intracellular uptake of low-density lipoprotein (LDL) by inhibiting the interaction between PGRMC1 and the LDL receptor (LDLR). Effects on other pathways cannot be excluded. Treatment with GlucoGL and CDDP significantly suppressed tumor growth following xenograft transplantation in mice. Collectively, this study indicates that GL derivatives are novel inhibitors of PGRMC1 that suppress cancer progression, and our findings provide new insights for cancer treatment.

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