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Mitochondria and their role in carcinogenesis
Bajzíková, Martina ; Neužil, Jiří (advisor) ; Masařík, Michal (referee) ; Mráček, Tomáš (referee)
(EN) Mitochondria are the principal intracellular organelles responsible for fuel generation; however, they are not just cell powerhouses but are involved in a range of other intracellular functions including cell metabolism, proliferation, death, and immune responses. Loss of function in mitochondria will result in oxidative stress, which is one of the underlying causal factors for a variety of diseases including cancer. Cancer cells can predominantly produce energy by glycolysis even in the presence of oxygen. This alternative metabolic behavior is known as the "Warburg Effect." Linked to this, cancer cell mitochondria can switch between glycolysis and oxidative phosphorylation (OXPHOS) for their energy requirements and survival. The electron transport chain (ETC) function is pivotal for mitochondrial respiration, which is also needed for dihydroorotate dehydrogenase (DHODH) activity that is essential for de novo pyrimidine synthesis. In our research, we have used respiration-deficient cancer cells to challenge the dogma that mitochondria with their DNA are constrained within cells in the body. Our results document that mitochondria move from normal cells within the tumor stroma to tumor cells without mitochondrial DNA (mtDNA), resulting in long-lasting recovery of mitochondrial functions and,...
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The Role of Tyrosine Kinase Activity of Mitochondrial ERBB2/HER2 in Breast Cancer
Novotná, Eliška ; Rohlena, Jakub (advisor) ; Vrbacký, Marek (referee)
Breast cancer is a common malignant disease affecting millions of women worldwide. Amplification of HER2 oncogene, a tyrosine kinase receptor, in breast cancer allows application of targeted therapy, but approximately one third of patients develop resistance to treatment. Relocalization of HER2 from the plasma membrane into the mitochondria was found and suggested as one of the potential causes of such resistance. Here we document that the function of mitochondrial HER2 is distinct from that of HER2 in the plasma membrane. Mitochondrial HER2 enhances cancer cell energetic metabolism, proliferation and migration in vitro, and tumour formation in vivo in mice correlating with elevated level of ROS signalling. The kinase activity of mitochondrial HER2 is unaffected, therefore I investigated its role in mitochondrial HER2 function. Moderate, endogenous levels of the kinase activity of mitochondrial HER2 drive pro-tumorigenic properties of breast cancer cells, while constitutive kinase activity sensitizes these cells to cell death and attenuates tumour formation in animal models. On the other hand, impairment of kinase activity due to mutation in the ATP binding site of mitochondrial HER2 supports adherence-independent growth in vitro and tumor growth in vivo. We propose that HER2 function in...
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Targeted cancer therapy based on altered metabolism of amino acids
Šafrhansová, Lucie ; Starková, Júlia (advisor) ; Zelenka, Jaroslav (referee)
The effects of targeted therapies in the treatment of cancer have been extensively researched and tested in many clinical trials. In contrast to conventional chemotherapy treatment, targeted therapy should act specifically on cancer cells with limited toxicity and lower risk of side effects. One type of targeted therapy exploits the Achilles heel of cancer - the specificity of tumour metabolism. With knowledge of the metabolic differences between tumor and normal cells, we can set up conditions that normal cells easily bridge, while tumor cells die as a result. This can be achieved by removing certain amino acids from the extracellular environment on which cancer cells depend. A well-known enzyme that has been used therapeutically for many years is asparaginase. However, asparaginase therapy is only successful in some cancers, so further development is needed, as well as the search for enzymes with similar effects. Over the years, four other enzymes that could become an integral part of the treatment of cancer patients in the future have been discovered - arginine deiminase, arginase, methioninase and cyst(e)inase. Past and current studies have investigated their effects on cancer cells in vitro and in vivo. Successful elimination of cancer cells often comes with limitations as immunogenicity and...
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The Role of Tyrosine Kinase Activity of Mitochondrial ERBB2/HER2 in Breast Cancer
Novotná, Eliška ; Rohlena, Jakub (advisor) ; Vrbacký, Marek (referee)
Breast cancer is a common malignant disease affecting millions of women worldwide. Amplification of HER2 oncogene, a tyrosine kinase receptor, in breast cancer allows application of targeted therapy, but approximately one third of patients develop resistance to treatment. Relocalization of HER2 from the plasma membrane into the mitochondria was found and suggested as one of the potential causes of such resistance. Here we document that the function of mitochondrial HER2 is distinct from that of HER2 in the plasma membrane. Mitochondrial HER2 enhances cancer cell energetic metabolism, proliferation and migration in vitro, and tumour formation in vivo in mice correlating with elevated level of ROS signalling. The kinase activity of mitochondrial HER2 is unaffected, therefore I investigated its role in mitochondrial HER2 function. Moderate, endogenous levels of the kinase activity of mitochondrial HER2 drive pro-tumorigenic properties of breast cancer cells, while constitutive kinase activity sensitizes these cells to cell death and attenuates tumour formation in animal models. On the other hand, impairment of kinase activity due to mutation in the ATP binding site of mitochondrial HER2 supports adherence-independent growth in vitro and tumor growth in vivo. We propose that HER2 function in...
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Horizontal transfer of mitochondria and its role in carcinogenesis
Nováková, Anna ; Neužil, Jiří (advisor) ; Rösel, Daniel (referee)
Mitochondria are essential organelles as they produce most ATP to support cellular activities, synthesize critical metabolic factors and are involved in lipid and phospholipid metabolism as well as calcium signalling. The oxidative phosphorylation (OXPHOS) system, present at the inner mitochondrial membrane, plays role in regulation of cellular metabolism and survival of cancer cells. Recent studies show importance of OXPHOS in growth of cancer cells via regulation of the de novo pyrimidine synthesis pathway. Dihydroorotate dehydrogenase (DHODH), a flavoprotein localized in the inner mitochondrial membrane, converts dihydroorotate (DHO) to orotate within the de novo pyrimidine synthesis pathway, generating electrons that are transferred, via redox- cycling of ubiquinone, to complex III (CIII) of respiratory chain. Since DHODH is functionally linked to CIII activity, impairment of respiration results in reduced activity of DHODH and pyrimidine synthesis. Therefore, mitochondrial damage or mutation in mitochondrial DNA (mtDNA) leads to decreased respiration, cancer cell proliferation and delay of tumour growth. As a compensation for damaged mitochondria, horizontal transfer of functional mitochondria from donor somatic cells to the mitochondria-damaged tumour cells was demonstrated. This...
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