Dichloroacetate induces autophagy in colorectal cancer cells and tumours.
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Date
2014-07-15ICR Author
Author
Lin, G
Hill, DK
Andrejeva, G
Boult, JKR
Troy, H
Fong, A-CLFWT
Orton, MR
Panek, R
Parkes, HG
Jafar, M
Koh, D-M
Robinson, SP
Judson, IR
Griffiths, JR
Leach, MO
Eykyn, TR
Chung, Y-L
Type
Journal Article
Metadata
Show full item recordAbstract
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.
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Subject
Cell Line, Tumor
HCT116 Cells
HT29 Cells
Animals
Humans
Mice
Mice, Nude
Colorectal Neoplasms
Reactive Oxygen Species
Lactic Acid
NAD
Microscopy, Electron
Random Allocation
Apoptosis
Autophagy
Female
TNF-Related Apoptosis-Inducing Ligand
TOR Serine-Threonine Kinases
Cell Cycle Checkpoints
Dichloroacetic Acid
Research team
Sarcoma Clinical Trials
Magnetic Resonance
Pre-Clinical MRI
Language
eng
Date accepted
2014-04-30
License start date
2014-07
Citation
British journal of cancer, 2014, 111 (2), pp. 375 - 385
Publisher
NATURE PUBLISHING GROUP