Fatima Baker, Halil Ibrahim Polat, Khalil Abou-El-Ardat, Islam Alshamleh, Marlyn Thölken, Daniel Hymon, Andrea Gubas, Sebastian E. Koschade-Rixner, Jonas B. Vischedyk, Manuel Kaulich, Harald Schwalbe, Shabnam Shaid, Christian Hubertus Brandts
- 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.
MetadatenAuthor: | Fatima BakerGND, Halil Ibrahim PolatORCiDGND, Khalil Abou-El-ArdatGND, Islam AlshamlehORCiDGND, Marlyn ThölkenORCiD, Daniel Hymon, Andrea GubasORCiD, Sebastian E. Koschade-RixnerORCiDGND, Jonas B. VischedykORCiD, Manuel KaulichORCiD, Harald SchwalbeORCiDGND, Shabnam ShaidGND, Christian Hubertus BrandtsORCiDGND |
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URN: | urn:nbn:de:hebis:30:3-745405 |
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DOI: | https://doi.org/10.3390/cancers13236142 |
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ISSN: | 2072-6694 |
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Parent Title (English): | Cancers |
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Publisher: | MDPI |
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Place of publication: | Basel |
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Document Type: | Article |
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Language: | English |
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Date of Publication (online): | 2021/12/06 |
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Date of first Publication: | 2021/12/06 |
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Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
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Release Date: | 2024/02/22 |
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Tag: | ATG3; acute myeloid leukemia; autophagy; autophagy inhibition; metabolic rewiring |
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Volume: | 13 |
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Issue: | 23, art. 6142 |
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Article Number: | 6142 |
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Page Number: | 19 |
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First Page: | 1 |
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Last Page: | 19 |
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Note: | 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. |
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HeBIS-PPN: | 522321453 |
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Institutes: | Medizin |
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| Wissenschaftliche Zentren und koordinierte Programme / Zentrum für Biomolekulare Magnetische Resonanz (BMRZ) |
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Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
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Sammlungen: | Universitätspublikationen |
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Licence (German): | Creative Commons - CC BY - Namensnennung 4.0 International |
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