title: Mitochondrial Phosphoenolpyruvate Carboxykinase Regulates Metabolic Adaptation and Enables Glucose-Independent Tumor Growth.
abstract: Cancer cells adapt metabolically to proliferate under nutrient limitation. Here we used combined transcriptional-metabolomic network analysis to identify metabolic pathways that support glucose-independent tumor cell proliferation. We found that glucose deprivation stimulated re-wiring of the tricarboxylic acid (TCA) cycle and early steps of gluconeogenesis to promote glucose-independent cell proliferation. Glucose limitation promoted the production of phosphoenolpyruvate (PEP) from glutamine via the activity of mitochondrial PEP-carboxykinase (PCK2). Under these conditions, glutamine-derived PEP was used to fuel biosynthetic pathways normally sustained by glucose, including serine and purine biosynthesis. PCK2 expression was required to maintain tumor cell proliferation under limited-glucose conditions in vitro and tumor growth in vivo. Elevated PCK2 expression is observed in several human tumor types and enriched in tumor tissue from non-small-cell lung cancer (NSCLC) patients. Our results define a role for PCK2 in cancer cell metabolic reprogramming that promotes glucose-independent cell growth and metabolic stress resistance in human tumors.
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada.
authors.forename: Emma E
authors.initials: EE
authors.lastname: Vincent
authors.affiliation: ITMO University, Saint Petersburg 197101, Russia; Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO 63110, USA.
authors.forename: Alexey
authors.initials: A
authors.lastname: Sergushichev
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada.
authors.forename: Takla
authors.initials: T
authors.lastname: Griss
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Gingras
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada.
authors.forename: Bozena
authors.initials: B
authors.lastname: Samborska
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Metabolomics Core Facility, Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada.
authors.forename: Thierry
authors.initials: T
authors.lastname: Ntimbane
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada.
authors.forename: Paula P
authors.initials: PP
authors.lastname: Coelho
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada.
authors.forename: Julianna
authors.initials: J
authors.lastname: Blagih
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Raissi
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Metabolomics Core Facility, Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada.
authors.forename: Luc
authors.initials: L
authors.lastname: Choinière
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Metabolomics Core Facility, Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Bridon
authors.affiliation: Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO 63110, USA.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Loginicheva
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada.
authors.forename: Breanna R
authors.initials: BR
authors.lastname: Flynn
authors.affiliation: School of Biochemistry, Medical Sciences Building, University of Bristol, Bristol BS8 1TD, UK.
authors.forename: Elaine C
authors.initials: EC
authors.lastname: Thomas
authors.affiliation: School of Biochemistry, Medical Sciences Building, University of Bristol, Bristol BS8 1TD, UK.
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Tavaré
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Metabolomics Core Facility, Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada.
authors.forename: Daina
authors.initials: D
authors.lastname: Avizonis
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada.
authors.forename: Arnim
authors.initials: A
authors.lastname: Pause
authors.affiliation: School of Biochemistry, Medical Sciences Building, University of Bristol, Bristol BS8 1TD, UK.
authors.forename: Douglas J E
authors.initials: DJ
authors.lastname: Elder
authors.affiliation: Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO 63110, USA. Electronic address: martyomov@pathology.wustl.edu.
authors.forename: Maxim N
authors.initials: MN
authors.lastname: Artyomov
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada. Electronic address: russell.jones@mcgill.ca.
authors.forename: Russell G
authors.initials: RG
authors.lastname: Jones
mesh_terms: D000222:Adaptation, Physiological / Q000235:genetics; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002952:Citric Acid Cycle / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D005943:Gluconeogenesis / Q000235:genetics*; D005947:Glucose / Q000172:deficiency; D005973:Glutamine / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D055432:Metabolomics; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010728:Phosphoenolpyruvate / Q000378:metabolism; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000235:genetics / Q000378:metabolism*; D011687:Purines / Q000096:biosynthesis; D019289:Pyruvic Acid / Q000378:metabolism; D012694:Serine / Q000096:biosynthesis
chemical_list: D011687:Purines; D005973:Glutamine; D012694:Serine; D010728:Phosphoenolpyruvate; D019289:Pyruvic Acid; C000597251:PCK2 protein, human; D019764:Phosphoenolpyruvate Carboxykinase (ATP); D005947:Glucose