title: The novel choline kinase inhibitor ICL-CCIC-0019 reprograms cellular metabolism and inhibits cancer cell growth.
abstract: The glycerophospholipid phosphatidylcholine is the most abundant phospholipid species of eukaryotic membranes and essential for structural integrity and signaling function of cell membranes required for cancer cell growth. Inhibition of choline kinase alpha (CHKA), the first committed step to phosphatidylcholine synthesis, by the selective small-molecule ICL-CCIC-0019, potently suppressed growth of a panel of 60 cancer cell lines with median GI50 of 1.12 μM and inhibited tumor xenograft growth in mice. ICL-CCIC-0019 decreased phosphocholine levels and the fraction of labeled choline in lipids, and induced G1 arrest, endoplasmic reticulum stress and apoptosis. Changes in phosphocholine cellular levels following treatment could be detected non-invasively in tumor xenografts by [18F]-fluoromethyl-[1,2-2H4]-choline positron emission tomography. Herein, we reveal a previously unappreciated effect of choline metabolism on mitochondria function. Comparative metabolomics demonstrated that phosphatidylcholine pathway inhibition leads to a metabolically stressed phenotype analogous to mitochondria toxin treatment but without reactive oxygen species activation. Drug treatment decreased mitochondria function with associated reduction of citrate synthase expression and AMPK activation. Glucose and acetate uptake were increased in an attempt to overcome the metabolic stress. This study indicates that choline pathway pharmacological inhibition critically affects the metabolic function of the cell beyond reduced synthesis of phospholipids.
authors.affiliation: Comprehensive Cancer Imaging Centre, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Trousil
authors.affiliation: Comprehensive Cancer Imaging Centre, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: Maciej
authors.initials: M
authors.lastname: Kaliszczak
authors.affiliation: Cancer Research UK, Beatson Institute, Garscube Estate, Glasgow, UK.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Schug
authors.affiliation: Comprehensive Cancer Imaging Centre, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: Quang-De
authors.initials: QD
authors.lastname: Nguyen
authors.affiliation: Comprehensive Cancer Imaging Centre, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Tomasi
authors.affiliation: Comprehensive Cancer Imaging Centre, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: Rosy
authors.initials: R
authors.lastname: Favicchio
authors.affiliation: Comprehensive Cancer Imaging Centre, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: Diana
authors.initials: D
authors.lastname: Brickute
authors.affiliation: Comprehensive Cancer Imaging Centre, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: Robin
authors.initials: R
authors.lastname: Fortt
authors.affiliation: Comprehensive Cancer Imaging Centre, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: Frazer J
authors.initials: FJ
authors.lastname: Twyman
authors.affiliation: Comprehensive Cancer Imaging Centre, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: Laurence
authors.initials: L
authors.lastname: Carroll
authors.affiliation: Comprehensive Cancer Imaging Centre, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Kalusa
authors.affiliation: Cellular Stress Group, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, Hammersmith Campus, London, UK.
authors.forename: Naveenan
authors.initials: N
authors.lastname: Navaratnam
authors.affiliation: Cellular Stress Group, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, Hammersmith Campus, London, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Adejumo
authors.affiliation: Cellular Stress Group, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, Hammersmith Campus, London, UK.
authors.forename: David
authors.initials: D
authors.lastname: Carling
authors.affiliation: Cancer Research UK, Beatson Institute, Garscube Estate, Glasgow, UK.
authors.forename: Eyal
authors.initials: E
authors.lastname: Gottlieb
authors.affiliation: Comprehensive Cancer Imaging Centre, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: Eric O
authors.initials: EO
authors.lastname: Aboagye
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D002794:Choline / Q000378:metabolism; D002797:Choline Kinase / Q000037:antagonists & inhibitors*; D002950:Citrate (si)-Synthase / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005260:Female; D005455:Fluorescent Antibody Technique; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D006801:Humans; D055432:Metabolomics; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D010713:Phosphatidylcholines / Q000378:metabolism*; D049268:Positron-Emission Tomography; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011726:Pyridinium Compounds / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000631:Aminopyridines; C000625798:ICL-CCIC-0019; D010713:Phosphatidylcholines; D047428:Protein Kinase Inhibitors; D011726:Pyridinium Compounds; D017382:Reactive Oxygen Species; D002950:Citrate (si)-Synthase; C517212:CHKA protein, human; D002797:Choline Kinase; D002794:Choline
keywords: cancer; choline kinase; metabolism; mitochondrial function; positron emission tomography