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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.

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Title
PGRMC1 phosphorylation affects cell shape, motility, glycolysis, mitochondrial form and function, and tumor growth
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
Publisher
BioMed Central
Date Issued
2020-04-03
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.
Subject
Mitochondria; Migration; Invasion; Metabolism; Cytochrome P450; Mesenchymal amoeboid transition; Proteomics; Tumor biology
Genre
Article
Type
Text
Language
eng
Date Available
2020-04-03
Provider
Vancouver : University of British Columbia Library
Rights
Attribution 4.0 International (CC BY 4.0)
DOI
10.14288/1.0389730
URI
http://hdl.handle.net/2429/73900
Affiliation
Pharmaceutical Sciences, Faculty of; Non UBC
Citation
BMC Molecular and Cell Biology. 2020 Apr 03;21(1):24
Publisher DOI
10.1186/s12860-020-00256-3
Peer Review Status
Reviewed
Scholarly Level
Faculty
Copyright Holder
The Author(s)
Rights URI
http://creativecommons.org/licenses/by/4.0/
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Attribution 4.0 International (CC BY 4.0)