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Cell response to genotoxic stress-based anti-cancer therapies
Imrichová, Terezie ; Hodný, Zdeněk (advisor) ; Rossmeislová, Lenka (referee) ; Rotrekl, Vladimír (referee)
The dissertation deals with a cell response to genotoxic stress, specifically to anti-cancer treatments with a genotoxic mechanism of action. In principle, cells can respond to these perturbing stimuli in several ways: in case of severe DNA damage, they usually undergo apoptosis or enter senescence. In case of minor DNA damage, or upon defective checkpoint mechanisms, they may continue the cell cycle, either with successfully repaired DNA or with mutations of various kind. Thanks to selection pressure, the mutations that provide cells with a certain growth advantage under conditions of continuing genotoxic stress, gradually accumulate and render the tumor treatment-resistant. In my thesis, I focus on several aspects of this whole process. First, I participated in a characterization of a radioresistant and anoikis-resistant population of prostate cancer cells. This population was generated by irradiating cells 35 times by 2 Gy, a regime used in clinics. After this treatment, a population of low-adherent cells emerged that demonstrated increased expression of EMT- and stem cell markers. The low-adherent state of these cells was maintained by Snail signaling and their anoikis resistance by ERK1/2 signaling. Interestingly, after a protracted period of time, these cells were able to re-adhere and...
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Cell response to genotoxic stress-based anti-cancer therapies
Imrichová, Terezie ; Hodný, Zdeněk (advisor) ; Rossmeislová, Lenka (referee) ; Rotrekl, Vladimír (referee)
The dissertation deals with a cell response to genotoxic stress, specifically to anti-cancer treatments with a genotoxic mechanism of action. In principle, cells can respond to these perturbing stimuli in several ways: in case of severe DNA damage, they usually undergo apoptosis or enter senescence. In case of minor DNA damage, or upon defective checkpoint mechanisms, they may continue the cell cycle, either with successfully repaired DNA or with mutations of various kind. Thanks to selection pressure, the mutations that provide cells with a certain growth advantage under conditions of continuing genotoxic stress, gradually accumulate and render the tumor treatment-resistant. In my thesis, I focus on several aspects of this whole process. First, I participated in a characterization of a radioresistant and anoikis-resistant population of prostate cancer cells. This population was generated by irradiating cells 35 times by 2 Gy, a regime used in clinics. After this treatment, a population of low-adherent cells emerged that demonstrated increased expression of EMT- and stem cell markers. The low-adherent state of these cells was maintained by Snail signaling and their anoikis resistance by ERK1/2 signaling. Interestingly, after a protracted period of time, these cells were able to re-adhere and...
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Odpověď metastatických buněčných linií karcinomu prostaty na genotoxický stres
Imrichová, Terezie ; Hodný, Zdeněk (advisor) ; Rösel, Daniel (referee)
Prostate cancer is the fourth most frequent cause of cancer-related deaths in men worldwide. One of current successful approaches to treat prostate cancer is radical prostatectomy followed by radiotherapy. However, this treatment is not 100% successful, as 53% patients develop secondary tumors. Our hypothesis is, that ionizing radiation itself contributes to the development of metastases by inducing changes in cell phenotype, particularly in terms of epithelial-to-mesenchymal transition and stemness. To test this hypothesis, we irradiated the cells of metastatic prostate cancer cell line DU145 by fractionated radiation 2 x 10 Gy and we compared the expression of selected epithelial, mesenchymal and stem-cell markers prior to and after irradiation. Besides we focused on a subpopulation of so called floating cells which arise during irradiation. These cells can survive the radiation treatment and after some time they are able to reattach and give rise to readherent population. We wanted to asses what is the cell cycle profile of these cells and whether and how fast they proliferate. In this thesis we have shown that radiation causes only minor changes in epithelial/mesenchymal and stem-like character of adherent fraction of the DU145 cell line. However, we have also described that small population of...
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Endogenous steroid dehydroepiandrosterone and its role in modulation of local metabolism of glucocorticoids
Imrichová, Terezie ; Pácha, Jiří (advisor) ; Kůs, Vladimír (referee)
The anti-glucocorticoid effect of dehydroepiandrosterone (DHEA) have been known for many years. However, its molecular basis have not been elucidated yet. The results of certain experiments suggest that not DHEA but its 7-oxygenated metabolites 7-OH-DHEA, 7-OH-DHEA a 7-oxo-DHEA are the antiglucocorticoid molecules. Various hypothesis about how these steroids exert their antiglucocorticoid action have been tested during the last several years. Some of them were reliably disproved (e.g. the competitive inhibition of glucocorticoid receptors), others were validated (e.g. the DHEA-mediated change in expression of certain enzymes participating in glucocorticoid metabolism), and yet others are still being considered. Nevertheless, clarifying the nature of the anti-glucocorticoid effect of DHEA or its metabolites is crucial for its possible use as a therapeutic drug.
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