title: Dichloroacetate induces autophagy in colorectal cancer cells and tumours.
abstract: BACKGROUND
  Dichloroacetate (DCA) has been found to have antitumour properties.
  
  
  METHODS
  We investigated the cellular and metabolic responses to DCA treatment and recovery in human colorectal (HT29, HCT116 WT and HCT116 Bax-ko), prostate carcinoma cells (PC3) and HT29 xenografts by flow cytometry, western blotting, electron microscopy, (1)H and hyperpolarised (13)C-magnetic resonance spectroscopy.
  
  
  RESULTS
  Increased expression of the autophagy markers LC3B II was observed following DCA treatment both in vitro and in vivo. We observed increased production of reactive oxygen species (ROS) and mTOR inhibition (decreased pS6 ribosomal protein and p4E-BP1 expression) as well as increased expression of MCT1 following DCA treatment. Steady-state lactate excretion and the apparent hyperpolarised [1-(13)C] pyruvate-to-lactate exchange rate (k(PL)) were decreased in DCA-treated cells, along with increased NAD(+)/NADH ratios and NAD(+). Steady-state lactate excretion and k(PL) returned to, or exceeded, control levels in cells recovered from DCA treatment, accompanied by increased NAD(+) and NADH. Reduced k(PL) with DCA treatment was found in HT29 tumour xenografts in vivo.
  
  
  CONCLUSIONS
  DCA induces autophagy in cancer cells accompanied by ROS production and mTOR inhibition, reduced lactate excretion, reduced k(PL) and increased NAD(+)/NADH ratio. The observed cellular and metabolic changes recover on cessation of treatment.
authors.affiliation: 1] Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research London and Royal Marsden Hospital, Sutton, Surrey SM2 5PT, UK [2] Department of Medical Imaging and Intervention, Chang Gung Memorial Hospital at Linkou, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan.
authors.forename: G
authors.initials: G
authors.lastname: Lin
authors.affiliation: Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research London and Royal Marsden Hospital, Sutton, Surrey SM2 5PT, UK.
authors.forename: D K
authors.initials: DK
authors.lastname: Hill
authors.affiliation: Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research London and Royal Marsden Hospital, Sutton, Surrey SM2 5PT, UK.
authors.forename: G
authors.initials: G
authors.lastname: Andrejeva
authors.affiliation: Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research London and Royal Marsden Hospital, Sutton, Surrey SM2 5PT, UK.
authors.forename: J K R
authors.initials: JK
authors.lastname: Boult
authors.affiliation: Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research London and Royal Marsden Hospital, Sutton, Surrey SM2 5PT, UK.
authors.forename: H
authors.initials: H
authors.lastname: Troy
authors.affiliation: Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research London and Royal Marsden Hospital, Sutton, Surrey SM2 5PT, UK.
authors.forename: A-C L F W T
authors.initials: AC
authors.lastname: Fong
authors.affiliation: Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research London and Royal Marsden Hospital, Sutton, Surrey SM2 5PT, UK.
authors.forename: M R
authors.initials: MR
authors.lastname: Orton
authors.affiliation: Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research London and Royal Marsden Hospital, Sutton, Surrey SM2 5PT, UK.
authors.forename: R
authors.initials: R
authors.lastname: Panek
authors.affiliation: Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research London and Royal Marsden Hospital, Sutton, Surrey SM2 5PT, UK.
authors.forename: H G
authors.initials: HG
authors.lastname: Parkes
authors.affiliation: Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research London and Royal Marsden Hospital, Sutton, Surrey SM2 5PT, UK.
authors.forename: M
authors.initials: M
authors.lastname: Jafar
authors.affiliation: Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research London and Royal Marsden Hospital, Sutton, Surrey SM2 5PT, UK.
authors.forename: D-M
authors.initials: DM
authors.lastname: Koh
authors.affiliation: Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research London and Royal Marsden Hospital, Sutton, Surrey SM2 5PT, UK.
authors.forename: S P
authors.initials: SP
authors.lastname: Robinson
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research London, Sutton, Surrey SM2 5NG, UK.
authors.forename: I R
authors.initials: IR
authors.lastname: Judson
authors.affiliation: CR-UK Cambridge Institute, Li Ka Shing Centre, Cambridge CB2 0RE, UK.
authors.forename: J R
authors.initials: JR
authors.lastname: Griffiths
authors.affiliation: Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research London and Royal Marsden Hospital, Sutton, Surrey SM2 5PT, UK.
authors.forename: M O
authors.initials: MO
authors.lastname: Leach
authors.affiliation: 1] Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research London and Royal Marsden Hospital, Sutton, Surrey SM2 5PT, UK [2] Division of Imaging Sciences and Biomedical Engineering, Kings College London, The Rayne Institute, St Thomas Hospital, London SE1 7EH, UK.
authors.forename: T R
authors.initials: TR
authors.lastname: Eykyn
authors.affiliation: Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research London and Royal Marsden Hospital, Sutton, Surrey SM2 5PT, UK.
authors.forename: Y-L
authors.initials: YL
authors.lastname: Chung
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D005260:Female; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008854:Microscopy, Electron; D009243:NAD / Q000378:metabolism; D011897:Random Allocation; D017382:Reactive Oxygen Species / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors
chemical_list: D017382:Reactive Oxygen Species; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D009243:NAD; D019344:Lactic Acid; D003999:Dichloroacetic Acid; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases