Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Honeder, S.
Lipid Hydrolysis in cancer metabolism
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medizinische Universität Graz; 2023. pp. 142
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Birner-Grünberger Ruth
- Brcic Luka
- Hrzenjak Andelko
- Altmetrics:
- Abstract:
- Cancer is among the leading causes of death worldwide, and together with cardiovascular diseases, it accounts for more than half of the global fatalities. Lung cancer is one of the most often diagnosed types of cancer and accounts for the highest number of cancer-related deaths. An important anticancer therapeutic strategy is the targeting of metabolic differences between tumor and normal cells. Cancer cells generally adapt their metabolism to support increased bioenergetic and biosynthetic demands, which is reflected in differentially regulated metabolic pathways. Cancer phenotypes like increased glucose uptake, higher glycolytic flux, as well as increased glutamine dependence, were already documented in the early to mid-20th century. In previous decades, changes in lipid metabolism like fatty acid uptake and synthesis have been described as emerging cancer phenotypes. The role of lipid catabolism, however, is less well explored in this context. The aim of this thesis is to study lipid hydrolysis in lung cancer, through investigating enzymes involved in intracellular lipid catabolism, and their influence on cancer progression and metabolism. In the first part of this thesis, we investigated the phenotype and proteome of a lung cancer cell line upon CRISPR-Cas9-mediated knockout of Adipose Triglyceride Lipase (ATGL), the rate-limiting enzyme of triglyceride catabolism from lipid droplets. We observed significantly increased proliferation and changes in metabolic proteins in cells lacking ATGL when grown in in-vivo-like cell culture models. Increased glucose uptake and lactate excretion, as well as higher levels of monounsaturated fatty acid species, in cells lacking ATGL corroborated the findings of the proteomics experiment that hint towards a more glycolytic phenotype and changes in lipid metabolism. Moreover, we investigated the phenotype and proteome of additional lung cancer cell lines that display lipolysis deficiency through knockout of ATGL or Monoglyceride Lipase (MGL), which is another enzyme involved in intracellular lipolysis. We found that the loss of ATGL caused lipid droplet accumulation in all tested cell lines, and in some but not all cell lines lipolysis deficiency caused significantly increased proliferation in 2D as well as 3D cell culture, independent of the lipase that is knocked out (ATGL or MGL). In the second part of this thesis, we aspired to investigate lipid hydrolysis in human lung tumors by means of multiple bioanalytic methods. We observed changes in gene expression of some lipases or lipase co-regulators. Furthermore, we discovered changes in the abundance and pattern of lipids- most strikingly a significant accumulation of triglycerides in tumors. Finally, proteomics analysis also revealed changes in proteins involved in triglyceride catabolism, with several lipases being lower abundant, as well as lower in activity in the lung tumors. Overall, our data point towards deregulated lipid hydrolysis in lung cancer, and we observe that loss of lipid hydrolases can result in metabolic changes and a concomitant more proliferative cancer phenotype.