Progesterone receptor membrane component 1 promotes survival of human breast cancer cells and the growth of xenograft tumors

Clark, Nicole C.; Friel, Anne M.; Pru, Cindy A.; Zhang, Ling; Shioda, Toshi; Rueda, Bo R.; Peluso, John J.; Pru, James K.

doi:10.1080/15384047.2016.1139240

Cited by 50 publications

(41 citation statements)

References 76 publications

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“…We were interested in whether DNA mutation rates may have been related to the P4-dependent protection against cell death, or to the mechanism of AG-205-induced cell death. Consistent with previously reported PGRMC1dependent anti-mitotic effects of P4 in Ishikawa endometrial cancer cells [36] and MDA-MB-231 breast cancer cells [47], incubation of cells in 1 μM P4 retarded cell proliferation of all cells over-expressing a PGRMC1-HA protein (WT, DM or TM), but not of MP cells relative to non-P4-treated control cells ( Fig. 2a).…”

Section: Pgrmc1 Phosphorylation Mutants Did Not Affect P4 or Ag-205 Rsupporting

confidence: 92%

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

Thejer

Adhikary

Teakel

et al. 2020

BMC Mol and Cell Biol

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Background: Progesterone receptor membrane component 1 (PGRMC1) is often elevated in cancers, and exists in alternative states of phosphorylation. A motif centered on PGRMC1 Y180 was evolutionarily acquired concurrently with the embryological gastrulation organizer that orchestrates vertebrate tissue differentiation.Results: Here, we show that mutagenic manipulation of PGRMC1 phosphorylation alters cell metabolism, genomic stability, and CpG methylation. Each of several mutants elicited distinct patterns of genomic CpG methylation. Mutation of S57A/Y180/S181A led to increased net hypermethylation, reminiscent of embryonic stem cells. Pathways enrichment analysis suggested modulation of processes related to animal cell differentiation status and tissue identity, as well as cell cycle control and ATM/ATR DNA damage repair regulation. We detected different genomic mutation rates in culture.Conclusions: A companion manuscript shows that these cell states dramatically affect protein abundances, cell and mitochondrial morphology, and glycolytic metabolism. We propose that PGRMC1 phosphorylation status modulates cellular plasticity mechanisms relevant to early embryological tissue differentiation.

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Section: Pgrmc1 Phosphorylation Mutants Did Not Affect P4 or Ag-205 Rsupporting

confidence: 92%

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

Thejer

Adhikary

Teakel

et al. 2020

BMC Mol and Cell Biol

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show abstract

“…We were interested in whether DNA mutation rates may have been related to the P4dependent protection against cell death, or to the mechanism of AG-205-indiced cell death. Consistent with previously reported PGRMC1-dependent anti-mitotic effects of P4 in Ishikawa endometrial cancer cells (Friel et al, 2015) and MDA-MB-231 breast cancer cells (Clark et al, 2016), incubation of cells in 1μM P4 retarded cell proliferation of all cells over-expressing a PGRMC1-HA protein (WT, DM or TM), but not of MP cells relative to non-P4-treated control cells ( Figure 3A). When cells pretreated with or without P4 for 1 hr were co-incubated in the presence doxorubicin (Dox), in the absence of P4 then WT, DM and TM cells were more susceptible to Dox-induced death ( Figure 3B-C, white data points and boxes), however these cells exhibited greater P4-dependent protection against Dox-induced death ( Figure 3B-C, shaded data points and boxes).…”

Section: Pgrmc1 Phosphorylation Mutants Did Not Affect P4 or Ag-205 Rsupporting

confidence: 92%

PGRMC1 phosphorylation and cell plasticity 2: genomic integrity and CpG methylation

et al. 2019

Preprint

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SUMMARYProgesterone receptor membrane component 1 (PGRMC1) is often elevated in cancers, and exists in alternative states of phosphorylation. A motif centered on PGRMC1 Y180 was evolutionarily acquired concurrently with the embryological gastrulation organizer that orchestrates vertebrate tissue differentiation. Here, we show that mutagenic manipulation of PGRMC1 phosphorylation alters cell metabolism, genomic stability, and CpG methylation. Each of several mutants elicited distinct patterns of genomic CpG methylation. Mutation of S57A/Y180/S181A led to increased net hypermethylation, reminiscent of embryonic stem cells. Pathways enrichment analysis suggested modulation of processes related to animal cell differentiation status and tissue identity, as well as cell cycle control and ATM/ATR DNA damage repair regulation. We detected different genomic mutation rates in culture. A companion manuscript shows that these cell states dramatically affect protein abundances, cell and mitochondrial morphology, and glycolytic metabolism. We propose that PGRMC1 phosphorylation status modulates cellular plasticity mechanisms relevant to early embryological tissue differentiation.

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“…This finding is in accordance with the experimental evidences that PGRMC1 depletion suppresses cancer cells proliferation in vitro and tumor growth in vivo in all the types of cancers studied so far. 10,19,[36][37][38] Moreover, the observation that PGRMC1 is overexpressed in a wide range of tumors when compared to corresponding normal tissues 19,[39][40][41][42] further support this hypothesis. In this view PGRMC1 overexpression would sustain propagation of abnormal cancer cells, helping them to escape mitotic catastrophe.…”

Section: Discussionsupporting

confidence: 63%

PGRMC1 participates in late events of bovine granulosa cells mitosis and oocyte meiosis

et al. 2016

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Progesterone Receptor Membrane Component 1 (PGRMC1) is expressed in both oocyte and ovarian somatic cells, where it is found in multiple cellular sub-compartments including the mitotic spindle apparatus. PGRMC1 localization in the maturing bovine oocytes mirrors its localization in mitotic cells, suggesting a possible common action in mitosis and meiosis. To test the hypothesis that altering PGRMC1 activity leads to similar defects in mitosis and meiosis, PGRMC1 function was perturbed in cultured bovine granulosa cells (bGC) and maturing oocytes and the effect on mitotic and meiotic progression assessed. RNA interference-mediated PGRMC1 silencing in bGC significantly reduced cell proliferation, with a concomitant increase in the percentage of cells arrested at G2/M phase, which is consistent with an arrested or prolonged M-phase. This observation was confirmed by time-lapse imaging that revealed defects in late karyokinesis. In agreement with a role during late mitotic events, a direct interaction between PGRMC1 and Aurora Kinase B (AURKB) was observed in the central spindle at of dividing cells. Similarly, treatment with the PGRMC1 inhibitor AG205 or PGRMC1 silencing in the oocyte impaired completion of meiosis I. Specifically the ability of the oocyte to extrude the first polar body was significantly impaired while meiotic figures aberration and chromatin scattering within the ooplasm increased. Finally, analysis of PGRMC1 and AURKB localization in AG205-treated oocytes confirmed an altered localization of both proteins when meiotic errors occur. The present findings demonstrate that PGRMC1 participates in late events of both mammalian mitosis and oocyte meiosis, consistent with PGRMC1's localization at the mid-zone and mid-body of the mitotic and meiotic spindle.

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Progesterone receptor membrane component 1 promotes survival of human breast cancer cells and the growth of xenograft tumors

Cited by 50 publications

References 76 publications

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

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

PGRMC1 phosphorylation and cell plasticity 2: genomic integrity and CpG methylation

PGRMC1 participates in late events of bovine granulosa cells mitosis and oocyte meiosis

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