PGRMC1 phosphorylation status and cell plasticity 1: glucose metabolism, mitochondria, and mouse xenograft tumorigenesis
PGRMC1 phosphorylation status and cell plasticity 1: glucose metabolism, mitochondria, and mouse xenograft tumorigenesis
ABSTRACT BackgroundProgesterone Receptor Membrane Component 1 (PGRMC1) is expressed in many cancer cells, where it is associated with detrimental patient outcomes. Multiple different functions and cellular locations have been attributed to PGRMC1 in a variety of contexts, however the mechanisms underlying PGRMC1 biology remain obscure. The protein contains several phosphorylated residues including tyrosines which were acquired in animal evolution prior to bilateral symmetry, and could be involved with animal cell differentiation mechanisms. ResultsHere we demonstrate that mutagenic manipulation of PGRMC1 phosphorylation status in MIA PaCa-2 pancreatic cells exerts broad pleiotropic effects, influencing cell plasticity and tumorigenicity, as assayed by cell biological and proteomics measurements. Relative to parental cells over-expressing hemagglutinin-tagged wild-type PGRMC1-HA, cells expressing a PGRMC1-HA-S57A/S181A double mutant 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 Rho-kinase inhibitor-sensitive changes including altered cell shape, motility, increased PI3K/Akt activity, and fragmented mitochondrial morphology. An S57A/Y180F/S181A triple mutant reduced PI3K/Akt activity, indicating involvement of Y180 in PI3K/Akt induction. Both triple mutant and Y180F single mutant cells exhibited attenuated mouse xenograft tumor growth. ConclusionsPhosphorylation status of the PGRMC1 tyrosine 180 regulatory motif exerts dramatic influence over cancer cell biology, including Warburg effect-like glucose metabolism. In accompanying papers we show that: 1) the cells examined here exhibit dramatically altered metabolism and epigenetic status, with the triple mutant inducing hypermethylation similar to that of embryonic stem cells, and that 2) Y180 was acquired in evolution concurrently with appearance of the organizer that induces animal gastrulation. Taken together, these results indicate that the undescribed mechanisms regulating PGRMC1 phosphorylation may be of great disease relevance and merit urgent investigation.
Turnbull Lynne、Kaur Amandeep、Poh Perlita、Pavy Megan、Zaw Thiri、Pawlak Michael、James Alexander C.、Roberts Tara L.、Fehm Tanja N.、Neubauer Hans、Cahill Michael A.、Thejer Bashar M.、Van Oosterum Ashleigh、Seth Ishith、Hannan Kate M.、Kinder Simon J.、Cassano Juan C.、Coorey Craig P.、Pajic Marina、Adhikary Partho P.、Pascovici Dana、Jazayeri Mitra、Molloy Mark P.、Weston Leslie A.、New Elizabeth J.、Teakel Sarah L.、Hannan Ross D.、Jazayeri Jalal A.、Ludescher Marina、Patrick Ellis、Goldys Ewa M.
The ithree institute, University of Technology SydneyUniversity of Sydney, School of Chemistry||University of Sydney, School of Medical SciencesACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical ResearchACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical ResearchAustralian Proteome Analysis Facility, Macquarie UniversityNMI Natural and Medical Sciences Institute at the University of TubingenIngham Institute for Applied Medical Research||School of Medicine, Western Sydney University||School of Medicine UNSW AustraliaIngham Institute for Applied Medical Research||School of Medicine, Western Sydney University||School of Medicine UNSW Australia||School of Medicine and University of Queensland Centre for Clinical ResearchDepartment of Gynecology and Obstetrics, University Women?ˉs Hospital of DusseldorfDepartment of Gynecology and Obstetrics, University Women?ˉs Hospital of DusseldorfSchool of Biomedical Sciences, Charles Sturt University||Department of Biochemistry and Molecular Biology, University of MelbourneSchool of Biomedical Sciences, Charles Sturt University||Department of Biology, College of Science, University of WasitLife Sciences and Health, Faculty of Science, Charles Sturt UniversitySchool of Biomedical Sciences, Charles Sturt UniversityDepartment of Biochemistry and Molecular Biology, University of Melbourne||ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical ResearchAXT Pty LtdParticles-Biology Interactions Laboratory, Department of Materials Meet Life, Swiss Federal Laboratories for Materials Science & Technology (Empa)Ingham Institute for Applied Medical Research||School of Medicine and University of Queensland Centre for Clinical ResearchThe Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research||St Vincent?ˉs Clinical School, Faculty of Medicine, University of NSWSchool of Biomedical Sciences, Charles Sturt University||Faculty of Pharmaceutical Sciences, The University of British ColumbiaAustralian Proteome Analysis Facility, Macquarie UniversityDepartment of Mathematics and Statistics, La Trobe UniversityAustralian Proteome Analysis Facility, Macquarie University||The Kolling Institute, The University of SydneyGraham Centre for Agricultural Innovation, Charles Sturt University||School of Agricultural and Wine Sciences, Charles Sturt UniversityUniversity of Sydney, School of ChemistrySchool of Biomedical Sciences, Charles Sturt UniversitySt Vincent?ˉs Clinical School, Faculty of Medicine, University of NSW||Department of Biochemistry and Molecular Biology, University of Melbourne||Division of Research, Peter MacCallum Cancer Centre||Sir Peter MacCallum Department of Oncology, University of Melbourne||Department of Biochemistry and Molecular Biology, Monash UniversitySchool of Biomedical Sciences, Charles Sturt UniversityDepartment of Gynecology and Obstetrics, University Women?ˉs Hospital of DusseldorfSchool of Mathematics and Statistics, University of SydneyARC Centre of Excellence for Nanoscale BioPhotonics, Macquarie University||The Graduate School of Biomedical Engineering, University of New South Wales
肿瘤学细胞生物学分子生物学
mitochondriamigrationinvasionorganizerembryologymetabolismcytochrome P450mesenchymal amoeboid transitionproteomics
Turnbull Lynne,Kaur Amandeep,Poh Perlita,Pavy Megan,Zaw Thiri,Pawlak Michael,James Alexander C.,Roberts Tara L.,Fehm Tanja N.,Neubauer Hans,Cahill Michael A.,Thejer Bashar M.,Van Oosterum Ashleigh,Seth Ishith,Hannan Kate M.,Kinder Simon J.,Cassano Juan C.,Coorey Craig P.,Pajic Marina,Adhikary Partho P.,Pascovici Dana,Jazayeri Mitra,Molloy Mark P.,Weston Leslie A.,New Elizabeth J.,Teakel Sarah L.,Hannan Ross D.,Jazayeri Jalal A.,Ludescher Marina,Patrick Ellis,Goldys Ewa M..PGRMC1 phosphorylation status and cell plasticity 1: glucose metabolism, mitochondria, and mouse xenograft tumorigenesis[EB/OL].(2025-03-28)[2025-08-02].https://www.biorxiv.org/content/10.1101/737718.点此复制
评论