Metabolic Rewiring Is Essential for AML Cell Survival to Overcome Autophagy Inhibition by Loss of ATG3
by
, , ,
Fatima Baker
1,2, 
Ibrahim H. Polat
1,
Khalil Abou-El-Ardat
1,2,3,
Islam Alshamleh
2,4,
Marlyn Thoelken
1,
Daniel Hymon
2,4,
Andrea Gubas
5,
Sebastian E. Koschade
1,2,3,5,
Jonas B. Vischedyk
1,3,
Manuel Kaulich
3,5,6,
Harald Schwalbe
2,4,
Shabnam Shaid
1,7,* and
Christian H. Brandts
1,2,3,7,* 1
Department of Medicine II, Hematology/Oncology, Goethe University, 60590 Frankfurt am Main, Germany
2
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
3
Frankfurt Cancer Institute, 60596 Frankfurt am Main, Germany
4
Center for Biomolecular Magnetic Resonance (BMRZ), Institute of Organic Chemistry and Chemical Biology, Goethe-University, 60438 Frankfurt am Main, Germany
5
Institute of Biochemistry II, Faculty of Medicine, Goethe University, 60590 Frankfurt am Main, Germany
6
Cardio-Pulmonary Institute, 60590 Frankfurt am Main, Germany
7
University Cancer Center Frankfurt (UCT), University Hospital, Goethe University, 60590 Frankfurt am Main, Germany
*
Authors to whom correspondence should be addressed.
Cancers 2021, 13(23), 6142; https://doi.org/10.3390/cancers13236142
Submission received: 15 October 2021
/
Revised: 25 November 2021
/
Accepted: 2 December 2021
/
Published: 6 December 2021
(This article belongs to the Special Issue Targeting Autophagy for Cancer Treatment)
Simple Summary
The importance of autophagy in leukemia progression and survival has been studied previously. However, little is known about the development of resistance mechanisms to autophagy inhibition in leukemia. Here, we present data on the mechanisms by which leukemia cells maintain their cell survival after inhibition of autophagy by the loss of ATG3. After the loss of ATG3, leukemia cells upregulated their energy metabolism by increasing glycolysis and mitochondrial metabolism, in particular oxidative phosphorylation, which resulted in higher ATP levels. Moreover, inhibition of mitochondrial function strongly impaired cell survival in ATG3 deficiency, thus demonstrating the importance of ATG3 in the regulation of metabolism and survival of leukemic cells. Therefore, our data provide a rationale for combining autophagy inhibitors with inhibitors targeting mitochondrial metabolism for the development of leukemia therapy to overcome the potential obstacle of emerging resistance to autophagy inhibition.
Abstract
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.
