TY  - JOUR
A1  - Baker, Fatima
A1  - Polat, Halil Ibrahim
A1  - Abou-El-Ardat, Khalil
A1  - Alshamleh, Islam
A1  - Thölken, Marlyn
A1  - Hymon, Daniel
A1  - Gubas, Andrea
A1  - Koschade-Rixner, Sebastian E.
A1  - Vischedyk, Jonas B.
A1  - Kaulich, Manuel
A1  - Schwalbe, Harald
A1  - Shaid, Shabnam
A1  - Brandts, Christian Hubertus
T1  - Metabolic rewiring is essential for AML cell survival to overcome autophagy inhibition by loss of ATG3
T2  - Cancers
N2  - Autophagy is an important survival mechanism that allows recycling of nutrients and removal of damaged organelles and has been shown to contribute to the proliferation of acute myeloid leukemia (AML) cells. However, little is known about the mechanism by which autophagy- dependent AML cells can overcome dysfunctional autophagy. In our study we identified autophagy related protein 3 (ATG3) as a crucial autophagy gene for AML cell proliferation by conducting a CRISPR/Cas9 dropout screen with a library targeting around 200 autophagy-related genes. shRNA-mediated loss of ATG3 impaired autophagy function in AML cells and increased their mitochondrial activity and energy metabolism, as shown by elevated mitochondrial ROS generation and mitochondrial respiration. Using tracer-based NMR metabolomics analysis we further demonstrate that the loss of ATG3 resulted in an upregulation of glycolysis, lactate production, and oxidative phosphorylation. Additionally, loss of ATG3 strongly sensitized AML cells to the inhibition of mitochondrial metabolism. These findings highlight the metabolic vulnerabilities that AML cells acquire from autophagy inhibition and support further exploration of combination therapies targeting autophagy and mitochondrial metabolism in AML.
KW  - autophagy
KW  - ATG3
KW  - autophagy inhibition
KW  - acute myeloid leukemia
KW  - metabolic rewiring
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/74540
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-745405
SN  - 2072-6694
N1  - This research was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)—Project-ID 259130777—SFB 1177. This work was supported in part by the LOEWE Center Frankfurt Cancer Institute (FCI) funded by the Hessen State Ministry for Higher Education, Research and the Arts [III L 5-519/03/03.001-(0015)]. Work at BMRZ is supported by the state of Hesse.
VL  - 13
IS  - 23, art. 6142
SP  - 1
EP  - 19
PB  - MDPI
CY  - Basel
ER  -