ATG7 regulates energy metabolism, differentiation and survival of Philadelphia chromosome-positive cells

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
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:Gottlieb, Professor Eyal and Baquero, Dr Pablo and Helgason, Dr Vignir and Holyoake, Professor Tessa and Mukhopadhyay, Dr Arunima and Mitchell, Dr Rebecca 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 > Institute 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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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
439231Is Bcr-Able expression relevant for the survival of cancer stem cells in chronic myeloid leukaemiaTessa HolyoakeMedical Research Council (MRC)G0600782RI CANCER SCIENCES
503112A randomised Phase II trial of Imatinib (IM) versus hydroxychloroquine (HCQ) with IM for patients with chronic myeloid leukaemia (CML) in cytogenic response (CyR)- CHOICESTessa HolyoakeMedical Research Council (MRC)G0900882RI CANCER SCIENCES
498551Key survival pathways in chronic myeloid leukaemia (cml) stem cells and novel approaches to their eradicationTessa HolyoakeCancer Research UK (CAN-RES-UK)11008RI CANCER SCIENCES
608811Autophagy Inhibition Combined with Targeted Therapy for Elimination of CML Stem Cells.Vignir HelgasonThe Kay Kendall Leukaemia Fund (KENDALL)KKL698RI CANCER SCIENCES
516251Targeting autophagy as a tool to potentiate Imatinib-induced cell death in CML cellsTessa HolyoakeKay Kendal Leukaemia Fund (KAY-KENDAL)KKL404RI CANCER SCIENCES
542691Development of a flow cytometry service within the Paul O'Gorman Leukaemia Research CentreAlison MichieThe Kay Kendall Leukaemia Fund (KENDALL)KKL501RI CANCER SCIENCES