PGRMC1 effects on metabolism, genomic mutation and CpG methylation imply crucial roles in animal biology and disease

Thejer, Bashar M.; Adhikary, Partho P.; Teakel, Sarah L.; Fang, Johnny; Weston, Paul A.; Gurusinghe, Saliya; Anwer, Ayad G.; Gosnell, Martin E.; Jazayeri, Jalal; Ludescher, Marina; Gray, Lesley-Ann; Pawlak, Michael; Wallace, Robyn H.; Pant, Sameer D.; Wong, Marie; Fischer, Tamás; New, Elizabeth J.; Fehm, Tanja; Neubauer, Hans; Goldys, Ewa M.; Quinn, Jane C.; Weston, Leslie A.; Cahill, Michael A.

doi:10.1186/s12860-020-00268-z

Cited by 20 publications

(45 citation statements)

References 92 publications

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“…This region has high predicted propensity to form coiled-coil protein interactions, and has recently been shown to share similarity with motifs in certain myosins (components of the actin cytoskeleton) (Hehenberger et al, 2020). Furthermore, PGRMC1 can be found in complexes with components of the actin cytoskeleton (Salsano et al, 2020;Thejer, Adhikary, Teakel, et al, 2020). Taken together, these results suggest that PGRMC1 modulation of the actin cytoskeleton could regulate actin-mediated mechanical forces required for vesicle trafficking.…”

Section: The Role Of the S2r Complex Protein Pgrmc1 In Health And Patmentioning

confidence: 83%

“…In human cancer cells, mutation of PGRMC1 phosphorylation sites leads to changes in PI3K/Akt activity, glucose metabolism, epigenetic genomic CpG methylation, and mitochondrial structure and function, leading to attenuated cancer growth and alterations to signaling pathways associated with pattern establishment and cell differentiation. Results reported by Dr. Cahill at the symposium have since been published (Thejer, Adhikary, Kaur, et al, 2020;Thejer, Adhikary, Teakel, et al, 2020). Perturbations in glucose metabolism, epigenetics and mitochondria are all symptoms of AD (Cenini and Voos, 2019;Ehrlich, 2019;Esposito and Sherr, 2019).…”

Section: The Role Of the S2r Complex Protein Pgrmc1 In Health And Patmentioning

confidence: 99%

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Proceedings from the Fourth International Symposium on σ-2 Receptors: Role in Health and Disease

Izzo

Colom‐Cadena

Riad

et al. 2020

eNeuro

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The sigma-2 receptor (S2R) complex has been implicated in central nervous system disorders ranging from anxiety and depression to neurodegenerative disorders such as Alzheimer's disease (AD). The proteins comprising the S2R complex impact processes including autophagy, cholesterol synthesis, progesterone signaling, lipid membrane-bound protein trafficking, and receptor stabilization at the cell surface. While there has been much progress in understanding the role of S2R in cellular processes and its potential therapeutic value, a great deal remains unknown. The International Symposium on Sigma-2 Receptors is held in conjunction with the annual Society for Neuroscience conference in order to promote collaboration and advance the field of S2R research. This review summarizes updates presented at the Fourth International Symposium on Sigma-2 Receptors: Role in Health and Disease, a Satellite Symposium held at the 2019 Society for Neuroscience (SfN) conference. Interdisciplinary members of the S2R research community presented both previously published and preliminary results from ongoing studies of the role of S2R in cellular metabolism, the anatomical and cellular expression patterns of S2R, the relationship between S2R and amyloid beta in AD, the role of S2R complex protein PGRMC1 in health and disease, and the efforts to design new S2R ligands for the purposes of research and drug development. The proceedings from this symposium are reported here as an update on the field of S2R research, as well as to highlight the value of the symposia that occur yearly in conjunction with the SfN conference.

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Section: The Role Of the S2r Complex Protein Pgrmc1 In Health And Patmentioning

confidence: 83%

Section: The Role Of the S2r Complex Protein Pgrmc1 In Health And Patmentioning

confidence: 99%

Proceedings from the Fourth International Symposium on σ-2 Receptors: Role in Health and Disease

Izzo

Colom‐Cadena

Riad

et al. 2020

eNeuro

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“…Importantly this investigation was extended to an in vivo system, specifically a subcutaneous mouse xenograft tumorigenesis model, in order to address the requirement of Y180 for tumor development in a complex environment. In a companion publication [36], we describe differences in metabolism, genomic mutation rates, and epigenetic genomic CpG methylation levels associated with the PGRMC1 phosphorylation mutants described in this present study.…”

Section: Introductionmentioning

confidence: 82%

PGRMC1 phosphorylation affects cell shape, motility, glycolysis, mitochondrial form and function, and tumor growth

Thejer

Adhikary

Kaur

et al. 2020

BMC Mol and Cell Biol

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Background Progesterone Receptor Membrane Component 1 (PGRMC1) is expressed in many cancer cells, where it is associated with detrimental patient outcomes. It contains phosphorylated tyrosines which evolutionarily preceded deuterostome gastrulation and tissue differentiation mechanisms. Results We demonstrate that manipulating PGRMC1 phosphorylation status in MIA PaCa-2 (MP) cells imposes broad pleiotropic effects. Relative to parental cells over-expressing hemagglutinin-tagged wild-type (WT) PGRMC1-HA, cells expressing a PGRMC1-HA-S57A/S181A double mutant (DM) exhibited reduced levels of proteins involved in energy metabolism and mitochondrial function, and altered glucose metabolism suggesting modulation of the Warburg effect. This was associated with increased PI3K/AKT activity, altered cell shape, actin cytoskeleton, motility, and mitochondrial properties. An S57A/Y180F/S181A triple mutant (TM) indicated the involvement of Y180 in PI3K/AKT activation. Mutation of Y180F strongly attenuated subcutaneous xenograft tumor growth in NOD-SCID gamma mice. Elsewhere we demonstrate altered metabolism, mutation incidence, and epigenetic status in these cells. Conclusions Altogether, these results indicate that mutational manipulation of PGRMC1 phosphorylation status exerts broad pleiotropic effects relevant to cancer and other cell biology.

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“…These phenotypic discrepancies in Pgrmc1 KO mutants may be due to the differences in model organisms, gene knockout strategy, and organ-specific roles of PGRMC1; nevertheless, it is obvious that PGRMC1 plays a critical role in female reproduction. Beside its classical function such as steroid hormone synthesis [ 26 , 27 ] and metabolic function as a non-genomic progesterone receptor [ 28 , 29 , 30 , 31 ], the relevance between Pgrmc1 and cancers has been suggested in diverse organs. One example is the role of Pgrmc1 in breast cancer [ 32 , 33 ], as Pgrmc1 has been recently identified to play important roles in the survival duration and metastasis of breast cancers in a murine PyMT model [ 34 ].…”

Section: Introductionmentioning

confidence: 99%

Loss of PGRMC1 Delays the Progression of Hepatocellular Carcinoma via Suppression of Pro-Inflammatory Immune Responses

Lee

Heo

et al. 2021

Cancers

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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.

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PGRMC1 effects on metabolism, genomic mutation and CpG methylation imply crucial roles in animal biology and disease

Cited by 20 publications

References 92 publications

Proceedings from the Fourth International Symposium on σ-2 Receptors: Role in Health and Disease

Proceedings from the Fourth International Symposium on σ-2 Receptors: Role in Health and Disease

PGRMC1 phosphorylation affects cell shape, motility, glycolysis, mitochondrial form and function, and tumor growth

Loss of PGRMC1 Delays the Progression of Hepatocellular Carcinoma via Suppression of Pro-Inflammatory Immune Responses

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