Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Tomin, T.
Role of adipose triglyceride lipase (ATGL) in cancer metabolism
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2018. pp.226.
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Birner-Grünberger Ruth
- Höfler Gerald
- Zebisch Armin
- Altmetrics:
- Abstract:
- Since the discovery of Otto Warburg in 1920s, alterations of metabolism in cancer became one of the main research topics in scientific community worldwide. By this end much is understood regarding the pivotal role of glycolysis in cancer, as well as the importance of lipid synthesis, uptake and oxidation. However, despite all advances we are still lacking a clear understanding of the function of lipid catabolism in cancer, especially the contribution of lipolysis to cancer metabolism. In the first part of this thesis I report that adipose triglyceride lipase (ATGL), a major triglyceride hydrolase, acts as tumor suppressor in lung cancer as its loss or inhibition renders lung cancer cells more aggressive. Deletion of ATGL with CRISPR/Cas9 induced accumulation of triacylglycerol (TG) rich lipid droplets (LD) with concomitant increase in pro-oncogenic signaling lipids and activation of proto-oncogene kinase SRC. SRC stimulated migration in A549 lung cancer cells lacking ATGL which could be reduced by treatment with a selective SRC inhibitor. Both activation of SRC and increase in migratory potential were abolished with lentiviral reintroduction of ATGL in the ATGL knock-out (ATGL-KO) cells. In addition, pharmacological inhibition of ATGL by atglistatin in murine lung cancer LLC1/LL2 and murine hepatocytes (AML-12) was sufficient to recapitulate the phenotype of SRC activation. The second part of this work is dedicated to assessment of oxidative stress. Oxidative stress contributes to progression of different pathologies, especially cancer, neurodegenerative and cardiovascular diseases. One of the common parameters for the evaluation of cellular redox stress is the ratio of reduced (GSH) to oxidized (GSSG) glutathione. I report a new method for accurate and robust measurement of both glutathione forms in one run using a two-step alkylation procedure and LC-MS/MS. The new method was applied and optimized for measurement of GSH/GSSG as a proxy for oxidative stress in cancer cells, blood and tissue samples. Moreover, GSH/GSSG in heart samples of patients suffering from cardiomyopathies was compared to non-failing hearts, which confirmed GSH/GSSG as potential marker for heart failure.