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

Bashar M Thejer; Partho P Adhikary; Amandeep Kaur; Sarah L Teakel; Ashleigh Van Oosterum; Ishith Seth; Marina Pajic; Katherine M Hannan; Megan Pavy; Perlita Poh; Jalal A Jazayeri; Thiri Zaw; Dana Pascovici; Marina Ludescher; Michael Pawlak; Juan C Cassano; Lynne Turnbull; Mitra Jazayeri; Alexander C James; Craig P Coorey; Tara L Roberts; Simon J Kinder; Ross D Hannan; Ellis Patrick; Mark P Molloy; Elizabeth J New; Tanja N Fehm; Hans Neubauer; Ewa M Goldys; Leslie A Weston; Michael A Cahill

doi:10.1186/s12860-020-00256-3

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

BMC Mol Cell Biol. 2020 Apr 3;21(1):24. doi: 10.1186/s12860-020-00256-3.

Authors

Bashar M Thejer^{1

2}, Partho P Adhikary^{1

3}, Amandeep Kaur^{4

5}, Sarah L Teakel¹, Ashleigh Van Oosterum⁶, Ishith Seth¹, Marina Pajic^{7

8}, Katherine M Hannan^{9

10}, Megan Pavy¹⁰, Perlita Poh¹⁰, Jalal A Jazayeri¹, Thiri Zaw¹¹, Dana Pascovici¹¹, Marina Ludescher¹², Michael Pawlak¹³, Juan C Cassano¹⁴, Lynne Turnbull^{15

16}, Mitra Jazayeri¹⁷, Alexander C James^{18

19

20}, Craig P Coorey^{18

21}, Tara L Roberts^{18

19

20

21}, Simon J Kinder²², Ross D Hannan^{9

10

23

24

25}, Ellis Patrick²⁶, Mark P Molloy^{11

27}, Elizabeth J New⁴, Tanja N Fehm¹², Hans Neubauer¹², Ewa M Goldys^{28

29}, Leslie A Weston^{30

31}, Michael A Cahill^{32

33}

Affiliations

¹ School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, NSW, 2650, Australia.
² Department of Biology, College of Science, University of Wasit, Wasit, 00964, Iraq.
³ Present address: Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, V6T 1Z4, Canada.
⁴ School of Chemistry, University of Sydney, Sydney, NSW, 2006, Australia.
⁵ Present address: School of Medical Sciences, University of Sydney, Sydney, NSW, 2006, Australia.
⁶ Life Sciences and Health, Faculty of Science, Charles Sturt University, Wagga Wagga, NSW, 2650, Australia.
⁷ The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, NSW, 2010, Australia.
⁸ St Vincent's Clinical School, Faculty of Medicine, University of NSW, Darlinghurst, 2010, NSW, Australia.
⁹ Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, 3010, Australia.
¹⁰ ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, ACT, Canberra, 2601, Australia.
¹¹ Australian Proteome Analysis Facility, Macquarie University, Sydney, NSW, 2109, Australia.
¹² Department of Gynecology and Obstetrics, University Women's Hospital of Dusseldorf, 40225, Dusseldorf, Germany.
¹³ NMI TT Pharmaservices, Protein Profiling, 72770, Reutlingen, Germany.
¹⁴ Particles-Biology Interactions Laboratory, Department of Materials Meet Life, Swiss Federal Laboratories for Materials Science & Technology (Empa), Lerchenfeldstrasse 5, CH-9014, St Gallen, Switzerland.
¹⁵ The ithree institute, University of Technology Sydney, Ultimo, NSW, 2007, Australia.
¹⁶ Present address: GE Healthcare Life Sciences, Issaquah, WA, 98027, USA.
¹⁷ Department of Mathematics and Statistics, La Trobe University, Melbourne, VIC, 3086, Australia.
¹⁸ Ingham Institute for Applied Medical Research, Liverpool, NSW, 2170, Australia.
¹⁹ School of Medicine, Western Sydney University, Locked Bag 1797, Penrith, NSW, 2751, Australia.
²⁰ South Western Sydney Clinical School, Faculty of Medicine, The University of New South Wales, Liverpool, NSW, 2170, Australia.
²¹ School of Medicine and University of Queensland Centre for Clinical Research, Herston, QLD, 4006, Australia.
²² AXT Pty Ltd, Warriewood (Sydney), NSW, 2102, Australia.
²³ Division of Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, 3000, Australia.
²⁴ Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, 3010, Australia.
²⁵ Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, 3168, Australia.
²⁶ School of Mathematics and Statistics, University of Sydney, Sydney, NSW, 2006, Australia.
²⁷ Present address: The Kolling Institute, The University of Sydney, St Leonards (Sydney), NSW, 2064, Australia.
²⁸ ARC Centre of Excellence for Nanoscale BioPhotonics, Macquarie University, Sydney, NSW, 2109, Australia.
²⁹ Present address: The Graduate School of Biomedical Engineering, University of New South Wales, Sydney, Kensington, NSW, 2052, Australia.
³⁰ Graham Centre for Agricultural Innovation, Charles Sturt University, Boorooma Street, Wagga Wagga, NSW, 2678, Australia.
³¹ School of Agricultural and Wine Sciences, Charles Sturt University, Boorooma Street, Wagga Wagga, NSW, 2678, Australia.
³² School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, NSW, 2650, Australia. mcahill@csu.edu.au.
³³ ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, ACT, Canberra, 2601, Australia. mcahill@csu.edu.au.

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.

Keywords: Cytochrome P450; Invasion; Mesenchymal amoeboid transition; Metabolism; Migration; Mitochondria; Proteomics; Tumor biology.

MeSH terms

Animals
Cell Line, Tumor
Cell Movement
Cell Proliferation
Cell Shape
Energy Metabolism
Glycolysis
Humans
Membrane Proteins / biosynthesis
Membrane Proteins / metabolism
Mice
Mice, Inbred NOD
Mice, SCID
Mitochondria / metabolism
Neoplasms
Phosphatidylinositol 3-Kinases / metabolism
Phosphorylation*
Receptors, Progesterone* / biosynthesis
Receptors, Progesterone* / metabolism

Substances

Membrane Proteins
PGRMC1 protein, human
PGRMC1 protein, mouse
Receptors, Progesterone

Abstract

MeSH terms

Substances

Grants and funding