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

• DOI: 10.21203/rs.2.22342/v3
• Publication Date: 2020-03-05T21:29:07Z
• Authors: Bashar M. Thejer; Partho P. Adhikary; Amandeep Kaur; Sarah L. Teakel; Ashleigh Van Oost...; 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.; Tanja N. Fehm; Hans Neubauer; Ewa M. Goldys; Leslie A. Weston; Michael CAHILL
• Keywords: tumors; Kinase; Putative Function; Biochemistry and cell biology not elsewhere classified; Expression; Cytochrome P450; Mice, SCID; 1307 Cell Biology; Mice; Phosphatidylinositol 3-Kinases; Bovine Granulosa-Cells; proteomics; Invasion; Cell Movement; Mice, Inbred NOD; Cell Line, Tumor; Neoplasms; XXXXXX - Unknown; 1312 Molecular Biology; Ovarian-Cancer Cells; Animals; Humans; Phosphorylation; Membrane Component 1; Cell Shape; Migration; Inhibition; Cell Proliferation; Protein Microarrays; Progression; QH573-671; phosphorylation; Membrane Proteins; glycolysis; Pancreatic-Cancer; Mitochondria; 3. Good health; mitochondria; Metabolism; motility; cancer cells; Mesenchymal amoeboid transition; Cytology; Energy Metabolism; Receptors, Progesterone; Glycolysis; Research Article

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.