Karvela, M. et al. (2016) ATG7 regulates energy metabolism, differentiation and survival of Philadelphia chromosome-positive cells. Autophagy, 12(6), pp. 936-948. (doi: 10.1080/15548627.2016.1162359) (PMID:27168493) (PMCID:PMC4922442)
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Abstract
A major drawback of tyrosine kinase inhibitor (TKI) treatment in chronic myeloid leukemia (CML) is that primitive CML cells are able to survive TKI-mediated BCR-ABL inhibition, leading to disease persistence in patients. Investigation of strategies aiming to inhibit alternative survival pathways in CML is therefore critical. We have previously shown that a nonspecific pharmacological inhibition of autophagy potentiates TKI-induced death in Philadelphia chromosome-positive cells. Here we provide further understanding of how specific and pharmacological autophagy inhibition affects nonmitochondrial and mitochondrial energy metabolism and reactive oxygen species (ROS)-mediated differentiation of CML cells and highlight ATG7 (a critical component of the LC3 conjugation system) as a potential specific therapeutic target. By combining extra- and intracellular steady state metabolite measurements by liquid chromatography-mass spectrometry with metabolic flux assays using labeled glucose and functional assays, we demonstrate that knockdown of ATG7 results in decreased glycolysis and increased flux of labeled carbons through the mitochondrial tricarboxylic acid cycle. This leads to increased oxidative phosphorylation and mitochondrial ROS accumulation. Furthermore, following ROS accumulation, CML cells, including primary CML CD34+ progenitor cells, differentiate toward the erythroid lineage. Finally, ATG7 knockdown sensitizes CML progenitor cells to TKI-induced death, without affecting survival of normal cells, suggesting that specific inhibitors of ATG7 in combination with TKI would provide a novel therapeutic approach for CML patients exhibiting persistent disease.
Item Type: | Articles |
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Additional Information: | This work was supported by Medical Research Council (G0600782 and G0900882, CHOICES, ISCRTN No. 61568166), the Kay Kendall Leukaemia Fund (KKL404 and KKL501), Glasgow Experimental Cancer Medicine Centre, which is funded by Cancer Research UK and by the Chief Scientist's Office (Scotland), Scottish Universities Life Science Alliance (MSD23_G_Holyoake-Chan), Scottish National Blood Transfusion Service, Cancer Research UK programme funding (C11074/A11008), G.V.H. is a KKLF Intermediate Research Fellow (KKL698)/Leadership Fellow. |
Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Holyoake, Professor Tessa and Mukhopadhyay, Dr Arunima and Mitchell, Dr Rebecca and Gottlieb, Professor Eyal and Baquero, Dr Pablo and Helgason, Professor Vignir and Karvela, Miss Maria |
Authors: | Karvela, M., Baquero, P., Kuntz, E. M., Mukhopadhyay, A., Mitchell, R., Allan, E. K., Chan, E., Kranc, K. R., Calabretta, B., Salomoni, P., Gottlieb, E., Holyoake, T. L., and Helgason, G. V. |
College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences |
Journal Name: | Autophagy |
Publisher: | Taylor and Francis |
ISSN: | 1554-8627 |
ISSN (Online): | 1554-8635 |
Published Online: | 11 May 2016 |
Copyright Holders: | Copyright © 2016 The Authors |
First Published: | First published in Autophagy |
Publisher Policy: | Reproduced under a Creative Commons License |
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