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Characterization and modulation of MitoTam-induced cell death in breast carcinoma cells
Hrysiuk, Mariia ; Anděra, Ladislav (advisor) ; Dráber, Peter (referee)
Although recent years brought many breakthrough discoveries in anti-cancer research and therapy, malignant diseases such as breast cancer (BC) still present one of the major health threats worldwide. Cancer cells usually gain resistance to the activation of regulated cell death (RCD) modalities such as caspase-dependent apoptosis. Among novel RCD-inducing agents belongs to mitochondria-targeted tamoxifen - MitoTam, which is also the major focus of this Thesis. In a panel of BC cells, we determined the energetic (mitochondrial respiration vs. glycolysis) and major RCD-related proteins (Western blotting) profiles, and using Lumascope LS720-assisted time-lapse monitoring we analyzed their sensitivity to MitoTam-induced RCD. We found out that glycolysis-preferring BC cells as MDA-MB-231 are more resistant to MitoTam treatment than mitochondrial respiration-biased MDA-MB-453 cells. However,the majority of tested BC cells can be sensitized to MitoTam by BH3 mimetics such as BCL-XL targeting A1155463 and some cellular metabolism-modulating compounds such as lactate dehydrogenase inhibitor (R)-GNE-140, especially in the pre-treatment regime. Also, other metabolism-modulating compounds such as Pyruvate Dehydrogenase Kinases inhibitor JX06 potently enhanced the efficacy and kinetics of MitoTam-induced RCD....
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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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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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