Progesterone Receptor Membrane Component 1 (Pgrmc1): A Heme-1 Domain Protein That Promotes Tumorigenesis and Is Inhibited by a Small Molecule

Ahmed, Ikhlas; Rohe, Hannah J.; Twist, Katherine E.; Mattingly, Marlene N.; Craven, Rolf J.

doi:10.1124/jpet.109.164210

Cited by 133 publications

(162 citation statements)

References 36 publications

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“…These results are in broad agreement with those obtained by Ahmed et al (2010a,b) using cancer cells, where PGRMC1 was shown to bind to EGFR and stabilize it on the plasma membrane, whereas AG205 decreased EGFR expression. Treatment with AG205 also inhibited cancer cell growth in these studies which is consistent with the known roles of both PGRMC1 and EGFR in promoting cancer growth and progression (Ono & Kuwano 2006, Ahmed et al 2010b. Thus, PGRMC1 acts as an adaptor protein regulating EGFR expression on the cell membranes of normal and malignant cells and promotes EGFR-dependent signaling in both health and disease.…”

Section: Discussionsupporting

confidence: 70%

“…Results of subsequent studies have indicated that AG205 binds to PGRMC1 and has a similar effect to that observed after treatment with Pgmrc1 siRNA in lung cancer cells, decreasing phosphorylation of ERK (Ahmed et al 2010b). Treatment with AG205 also decreases EGFR-dependent signaling in lung cancer cells, consistent with the proposed role of PGRMC1 as a binding partner with EGFR (Ahmed et al 2010a).…”

Section: Introductionsupporting

confidence: 61%

“…Treatment with AG205 alone, and in combination with these treatments, also decreased membrane Pgrmc1 expression, but this was not accompanied by increases in GVBD, which indicates that the inhibitor directly influences cell surface expression of Pgrmc1. In contrast, a concentration-dependent increase in whole-cell PGRMC1 protein concentrations was observed in experiments on lung cancer cells after treatment with AG205 (Ahmed et al 2010b). The mechanisms by which AG205 alters PGRMC1 expression are unclear but may be associated with alterations in signaling, trafficking, and degradation of the protein once it interacts with AG205.…”

Section: Discussionmentioning

confidence: 58%

“…The mechanisms by which AG205 alters PGRMC1 expression are unclear but may be associated with alterations in signaling, trafficking, and degradation of the protein once it interacts with AG205. However, these AG205-induced changes in PGRMC1 expression are unlikely to have any functional significance because, as shown previously (Ahmed et al 2010b), AG205 inhibits PGRMC1 functions directly through binding to its heme-binding domain, so that the immunoreactive PGRMC1 detected in cells largely represents an inactive form of the protein.…”

Section: Discussionmentioning

confidence: 98%

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

Aizen¹,

Thomas²

2015

Journal of Endocrinology

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The regulation of receptor trafficking to the cell surface and its effect on responses of target cells to growth factors and hormones remain poorly understood. Initial evidence has been recently obtained using cancer cells that surface expression of the epidermal growth factor receptor (EGFR) is dependent on its association with progesterone receptor membrane component 1 (PGRMC1). Estrogen inhibition of oocyte maturation (OM) in zebrafish is mediated through G-protein-coupled estrogen membrane receptor 1 (Gper1) and involves activation of Egfr. Therefore, in this study, the potential roles of Pgrmc1 in the cell surface expression and functions of Egfr in normal cells were investigated in this in vitro OM model of Egfr action using an inhibitor of PGMRC1 signaling, AG205. A single w60 kDa protein band, which corresponds to the size of the Pgrmc1 dimer, was detected on plasma membranes of fully grown oocytes by western blotting. Co-treatment with the PGRMC1 inhibitor AG205 (20 mM) blocked the inhibitory effects of 100 nM estradiol-17b and the GPER agonist, G-1, on spontaneous maturation of denuded zebrafish oocytes. Moreover, reversal of these estrogen effects on OM by the EGFR inhibitors AG1478 and AG825 (50 mM) was prevented by co-incubation with the PGRMC1 inhibitor. Inhibition of Pgrmc1 signaling with AG205 also caused a decrease in Egfr-dependent signaling and Egfr expression on oocyte cell membranes. These results indicate that maintenance of Pgrmc1 signaling is required for Egfr expression on zebrafish oocyte cell membranes and for conserving the functions of Egfr in maintaining meiotic arrest through estrogen activation of Gper.

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Section: Discussionsupporting

confidence: 70%

Section: Introductionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 98%

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

Aizen¹,

Thomas²

2015

Journal of Endocrinology

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“…PGRMC1 expression is elevated in several cancer cells like lung, breast, and ovarian cancer (3)(4)(5). Further, in ovarian cancer PGRMC1 expression is increased in advanced cancer stages (3).…”

Section: Introductionmentioning

confidence: 96%

Involvement of let-7/miR-98 microRNAs in the regulation of progesterone receptor membrane component 1 expression in ovarian cancer cells

Wendler¹

2010

Oncol Rep

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Abstract. PGRMC1 (progesterone receptor membrane component 1) is part of a multi-protein complex, that is highly expressed in several cancers and is involved in chemoresistance. Although PGRMC1 plays an important role in various cancers, little is known about how PGRMC1 expression is regulated. Therefore, the present study was designed to elucidate the molecular mechanisms that influence PGRMC1 expression in ovarian cancer cells. An in silico approach revealed that the 3'-untranslated region of PGRMC1 contains one highly and one poorly conserved binding site for the microRNA let-7/miR-98 and one highly conserved binding site for miR-141/200a. Luciferase assays and real-time PCRs showed that the let-7 isoforms let-7i and miR-98 target PGRMC1 in SKOV-3 cells. In contrast, the conserved binding site for miR-200a/141 in the 3'-UTR of PGRMC1 is not functional. Stimulation of SKOV-3 cells with progesterone resulted in a decrease in PGRMC1 mRNA levels. Further, an analysis of endogenous let-7i levels in SKOV-3 cells revealed that let-7i expression increased after stimulation with progesterone. Therefore, progesterone may exert its effect on PGRMC1 expression in part by stimulation of let-7i. In conclusion, we propose that PGRMC1 expression is regulated by the miRNAs let-7/miR-98, which could become therapeutic targets, as PGRMC1, like many other targets of let-7, seems to be involved in cancer proliferation and chemotherapy resistance.

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

Mir

Ahmed

Arnold

et al. 2011

Intl Journal of Cancer

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Cancer is one of the leading causes of death, and there is an urgent need for new biomarkers and therapeutic targets. The progesterone receptor membrane component 1 (Pgrmc1) protein is upregulated in multiple types of cancer, and Pgrmc1 is required for tumor cell proliferation, motility and tumor formation in vivo. Furthermore, a small molecule inhibitor of Pgrmc1 suppressed the growth of lung, breast and cervical cancer cell lines. Recently, Pgrmc1 was identified as the sigma‐2 receptor, a putative type of opioid receptor, and sigma‐2 receptors are induced in cancers. However, Pgrmc1 shares no homology with known opioid or hormone receptors but is related to cytochrome b5, and Pgrmc1 binds to heme and has reducing activity. In this study, we have analyzed Pgrmc1 levels in clinical tumor samples from squamous cell lung cancers (SCLC) and lung adenocarcinomas compared to corresponding nonmalignant tissue. Pgrmc1 levels increased significantly (p ≤ 0.05) in 12/15 SCLC samples and was elevated in poorly differentiated tumors. Pgrmc1 was highly expressed in SCLC cell lines, and SCLC cell survival was inhibited by siRNA knockdown of Pgrmc1 or the Pgrmc1 inhibitor AG‐205. In adenocarcinomas, 6/15 tumors significantly had elevated Pgrmc1 levels, which correlated with patient survival. Pgrmc1 localizes to secretory vesicles in cancer cells, and Pgrmc1 was secreted by lung cancer cells. Furthermore, Pgrmc1 was significantly elevated in the plasma of lung cancer patients compared to noncancer patients. Together, the results demonstrate that Pgrmc1 is a potential tumor and serum biomarker, as well as a therapeutic target, for lung cancer.

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Progesterone Receptor Membrane Component 1 (Pgrmc1): A Heme-1 Domain Protein That Promotes Tumorigenesis and Is Inhibited by a Small Molecule

Cited by 133 publications

References 36 publications

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

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

Involvement of let-7/miR-98 microRNAs in the regulation of progesterone receptor membrane component 1 expression in ovarian cancer cells

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

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