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PGRMC1 phosphorylation affects cell shape, motility, glycolysis, mitochondrial form and function, and tumor growth Thejer, Bashar M; Adhikary, Partho P; Kaur, Amandeep; Teakel, Sarah L; Van Oosterum, Ashleigh; Seth, Ishith; Pajic, Marina; Hannan, Katherine M; Pavy, Megan; Poh, Perlita; et al.
Abstract
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.
Item Metadata
Title |
PGRMC1 phosphorylation affects cell shape, motility, glycolysis, mitochondrial form and function, and tumor growth
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Creator |
Thejer, Bashar M; Adhikary, Partho P; Kaur, Amandeep; Teakel, Sarah L; Van Oosterum, Ashleigh; Seth, Ishith; Pajic, Marina; Hannan, Katherine M; Pavy, Megan; Poh, Perlita; Jazayeri, Jalal A; Zaw, Thiri; Pascovici, Dana; Ludescher, Marina; Pawlak, Michael; Cassano, Juan C; Turnbull, Lynne; Jazayeri, Mitra; James, Alexander C; Coorey, Craig P; Roberts, Tara L; Kinder, Simon J; Hannan, Ross D; Patrick, Ellis; Molloy, Mark P; New, Elizabeth J; Fehm, Tanja N; Neubauer, Hans; Goldys, Ewa M; Weston, Leslie A; Cahill, Michael A
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Publisher |
BioMed Central
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Date Issued |
2020-04-03
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Description |
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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Language |
eng
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Date Available |
2020-04-03
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Provider |
Vancouver : University of British Columbia Library
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Rights |
Attribution 4.0 International (CC BY 4.0)
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DOI |
10.14288/1.0389730
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URI | |
Affiliation | |
Citation |
BMC Molecular and Cell Biology. 2020 Apr 03;21(1):24
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Publisher DOI |
10.1186/s12860-020-00256-3
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Peer Review Status |
Reviewed
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Scholarly Level |
Faculty
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Copyright Holder |
The Author(s)
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Aggregated Source Repository |
DSpace
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Item Citations and Data
Rights
Attribution 4.0 International (CC BY 4.0)