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Cancers
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The Role of PGRMC1 and PGRMC2 in Metabolism and Cancer...
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The Role of PGRMC1 and PGRMC2 in Metabolism and Cancer Biology

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (31 January 2022) | Viewed by 25503

Special Issue Editors

Dr. Michael A. Cahill

E-Mail Website
Guest Editor
School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, NSW 2650, Australia
Interests: PGRMC1 phosphorylation; signaling; metabolism; discovery proteomics; protein evolution and PGRMC1 cell biology
Prof. Dr. Hans Neubauer

E-Mail Website
Guest Editor
Department of Gynecology and Obstetrics, University Women's Hospital of Dusseldorf, 40225 Dusseldorf, Germany
Interests: PGRMC1; liquid Biopsy; breast cancer; circulating tumor cells

Special Issue Information

Dear Colleagues,

Progesterone receptor membrane component 1 (PGRMC1) is a small protein with a perplexing the diversity of potential functions. It belongs to the membrane-associated progesterone receptor (MAPR) family, which—in mammals—consists of PGRMC1, PGRMC2, neuferricin, and neudesin.

PGRMC1 affects biological functions such as cholesterol/steroid biosynthesis and metabolism, iron homeostasis and heme trafficking, autophagy, regulation of cell cycle and proliferation, and cell migration and invasion. Less is known about the functions of PGRMC2, but due to its >50% identity similarity to PGRMC1, both may share overlapping functions and roles.

PGRMC1 has been confirmed to play a role in carcinogenesis and may therefore represent a target for cancer therapy. The PGRMC1 protein and mRNA are upregulated in malignancies including colon, lung, ovary, cervix, and breast. Expression of PGRMC1 correlates with metastasis to lymph nodes, larger tumor size, and poor overall and tumor-free survival. One important feature is its interaction with cytochrome P450 enzymes (CYPs), which catalyze the metabolism of both endogenous and exogenous substances. This enormous spectrum of metabolic pathways may explain PGRMC1’s many postulated roles and may position it as an integrator of external influences, such as life-style factors and cancer development. One such metabolic pathway is represented by the cholesterol pathway. There are increasing data published that its metabolites affect tumor development, therapy resistance, and metastasis.

With this Special Issue, we would like to highlight the roles of PGRMC1 and PGRMC2 in cancer development or therapy resistance, with a special focus on potential functions of both in metabolic pathways affecting cancer biology. We encourage submission of manuscripts covering both basic and more (pre)clinical aspects that advance our understanding of targeting PGRMC1 and PGRMC2 in human tumors.

Dr. Michael A. Cahill
Prof. Dr. Hans Neubauer
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • PGRMC1
  • PGRMC2
  • CYPs
  • metabolism
  • cancer development
  • therapy resistance
  • metastasis

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Published Papers (6 papers)

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Editorial

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8 pages, 250 KiB  
Editorial
PGRMC Proteins Are Coming of Age: A Special Issue on the Role of PGRMC1 and PGRMC2 in Metabolism and Cancer Biology
by Michael A. Cahill and Hans Neubauer
Cancers 2021, 13(3), 512; https://doi.org/10.3390/cancers13030512 - 29 Jan 2021
Cited by 21 | Viewed by 3191
Abstract
This is a preface by the guest editors of the special issue of Cancers featuring the biology of progesterone (P4) receptor membrane component (PGRMC) proteins as it relates to metabolism and cancer [...] Full article
(This article belongs to the Special Issue The Role of PGRMC1 and PGRMC2 in Metabolism and Cancer Biology)

Research

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22 pages, 2701 KiB  
Article
PGRMC1 Promotes Progestin-Dependent Proliferation of Breast Cancer Cells by Binding Prohibitins Resulting in Activation of ERα Signaling
by Yingxue Bai, Marina Ludescher, Gereon Poschmann, Kai Stühler, Martine Wyrich, Julia Oles, André Franken, Mahdi Rivandi, Anna Abramova, Florian Reinhardt, Eugen Ruckhäberle, Dieter Niederacher, Tanja Fehm, Michael A. Cahill, Nadia Stamm and Hans Neubauer
Cancers 2021, 13(22), 5635; https://doi.org/10.3390/cancers13225635 - 11 Nov 2021
Cited by 22 | Viewed by 3518
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue The Role of PGRMC1 and PGRMC2 in Metabolism and Cancer Biology)
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22 pages, 4523 KiB  
Article
Glycyrrhizin Derivatives Suppress Cancer Chemoresistance by Inhibiting Progesterone Receptor Membrane Component 1
by Yasuaki Kabe, Ikko Koike, Tatsuya Yamamoto, Miwa Hirai, Ayaka Kanai, Ryogo Furuhata, Hitoshi Tsugawa, Erisa Harada, Kenji Sugase, Kazue Hanadate, Nobuji Yoshikawa, Hiroaki Hayashi, Masanori Noda, Susumu Uchiyama, Hiroki Yamazaki, Hirotoshi Tanaka, Takuya Kobayashi, Hiroshi Handa and Makoto Suematsu
Cancers 2021, 13(13), 3265; https://doi.org/10.3390/cancers13133265 - 29 Jun 2021
Cited by 24 | Viewed by 5302
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue The Role of PGRMC1 and PGRMC2 in Metabolism and Cancer Biology)
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19 pages, 2082 KiB  
Article
Loss of PGRMC1 Delays the Progression of Hepatocellular Carcinoma via Suppression of Pro-Inflammatory Immune Responses
by Sang R. Lee, Jong Geol Lee, Jun H. Heo, Seong Lae Jo, Jihoon Ryu, Globinna Kim, Jung-Min Yon, Myeong Sup Lee, Geun-Shik Lee, Beum-Soo An, Hyun-Jin Shin, Dong-Cheol Woo, In-Jeoung Baek and Eui-Ju Hong
Cancers 2021, 13(10), 2438; https://doi.org/10.3390/cancers13102438 - 18 May 2021
Cited by 17 | Viewed by 4064
Abstract
Pgrmc1 is a non-canonical progesterone receptor related to the lethality of various types of cancer. PGRMC1 has been reported to exist in co-precipitated protein complexes with epidermal growth factor receptor (EGFR), which is considered a useful therapeutic target in hepatocellular carcinoma (HCC). Here, [...] Read more.
Pgrmc1 is a non-canonical progesterone receptor related to the lethality of various types of cancer. PGRMC1 has been reported to exist in co-precipitated protein complexes with epidermal growth factor receptor (EGFR), which is considered a useful therapeutic target in hepatocellular carcinoma (HCC). Here, we investigated whether Pgrmc1 is involved in HCC progression. In clinical datasets, PGRMC1 transcription level was positively correlated with EGFR levels; importantly, PGRMC1 level was inversely correlated with the survival duration of HCC patients. In a diethylnitrosamine (DEN)-induced murine model of HCC, the global ablation of Pgrmc1 suppressed the development of HCC and prolonged the survival of HCC-bearing mice. We further found that increases in hepatocyte death and suppression of compensatory proliferation in the livers of DEN-injured Pgrmc1-null mice were concomitant with decreases in nuclear factor κB (NF-κB)-dependent production of interleukin-6 (IL-6). Indeed, silencing of Pgrmc1 in murine macrophages led to reductions in NF-κB activity and IL-6 production. We found that the anti-proinflammatory effect of Pgrmc1 loss was mediated by reductions in EGFR level and its effect was not observed after exposure of the EGFR inhibitor erlotinib. This study reveals a novel cooperative role of Pgrmc1 in supporting the EGFR-mediated development of hepatocellular carcinoma, implying that pharmacological suppression of Pgrmc1 may be a useful strategy in HCC treatment. Full article
(This article belongs to the Special Issue The Role of PGRMC1 and PGRMC2 in Metabolism and Cancer Biology)
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Review

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23 pages, 4604 KiB  
Review
Insights on the Role of PGRMC1 in Mitotic and Meiotic Cell Division
by Valentina Lodde, Rodrigo Garcia Barros, Laura Terzaghi, Federica Franciosi and Alberto Maria Luciano
Cancers 2022, 14(23), 5755; https://doi.org/10.3390/cancers14235755 - 23 Nov 2022
Cited by 5 | Viewed by 3255
Abstract
During mitosis, chromosome missegregation and cytokinesis defects have been recognized as hallmarks of cancer cells. Cytoskeletal elements composing the spindle and the contractile ring and their associated proteins play crucial roles in the faithful progression of mitotic cell division. The hypothesis that PGRMC1, [...] Read more.
During mitosis, chromosome missegregation and cytokinesis defects have been recognized as hallmarks of cancer cells. Cytoskeletal elements composing the spindle and the contractile ring and their associated proteins play crucial roles in the faithful progression of mitotic cell division. The hypothesis that PGRMC1, most likely as a part of a yet-to-be-defined complex, is involved in the regulation of spindle function and, more broadly, the cytoskeletal machinery driving cell division is particularly appealing. Nevertheless, more than ten years after the preliminary observation that PGRMC1 changes its localization dynamically during meiotic and mitotic cell division, this field of research has remained a niche and needs to be fully explored. To encourage research in this fascinating field, in this review, we will recap the current knowledge on PGRMC1 function during mitotic and meiotic cell division, critically highlighting the strengths and limitations of the experimental approaches used so far. We will focus on known interacting partners as well as new putative associated proteins that have recently arisen in the literature and that might support current as well as new hypotheses of a role for PGRMC1 in specific spindle subcompartments, such as the centrosome, kinetochores, and the midzone/midbody. Full article
(This article belongs to the Special Issue The Role of PGRMC1 and PGRMC2 in Metabolism and Cancer Biology)
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21 pages, 33157 KiB  
Review
Progesterone Receptor Membrane Component (PGRMC)1 and PGRMC2 and Their Roles in Ovarian and Endometrial Cancer
by John J. Peluso and James K. Pru
Cancers 2021, 13(23), 5953; https://doi.org/10.3390/cancers13235953 - 26 Nov 2021
Cited by 25 | Viewed by 4170
Abstract
Cancers of the female reproductive tract are both lethal and highly prevalent. For example, the five-year survival rate of women diagnosed with ovarian cancer is still less than 50%, and endometrial cancer is the fourth most common cancer in women with > 65,000 [...] Read more.
Cancers of the female reproductive tract are both lethal and highly prevalent. For example, the five-year survival rate of women diagnosed with ovarian cancer is still less than 50%, and endometrial cancer is the fourth most common cancer in women with > 65,000 new cases in the United States in 2020. Among the many genes already established as key participants in ovarian and endometrial oncogenesis, progesterone receptor membrane component (PGRMC)1 and PGRMC2 have gained recent attention given that there is now solid correlative information supporting a role for at least PGRMC1 in enhancing tumor growth and chemoresistance. The expression of PGRMC1 is significantly increased in both ovarian and endometrial cancers, similar to that reported in other cancer types. Xenograft studies using human ovarian and endometrial cancer cell lines in immunocompromised mice demonstrate that reduced expression of PGRMC1 results in tumors that grow substantially slower. While the molecular underpinnings of PGRMCs’ mechanisms of action are not clearly established, it is known that PGRMCs regulate survival pathways that attenuate stress-induced cell death. The objective of this review is to provide an overview of what is known about the roles that PGRMC1 and PGRMC2 play in ovarian and endometrial cancers, particularly as related to the mechanisms through which they regulate mitosis, apoptosis, chemoresistance, and cell migration. Full article
(This article belongs to the Special Issue The Role of PGRMC1 and PGRMC2 in Metabolism and Cancer Biology)
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