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Mechanisms of anticancer drug action in neuroblastomas
Groh, Tomáš ; Stiborová, Marie (advisor) ; Levová, Kateřina (referee) ; Vališ, Karel (referee)
Cancer cells are able to adapt to different stress factors such as hypoxia, which is caused by insufficient tumor vascularization. An increased acetylation status of histones H3 and H4 in UKF-NB-3 and UKF-NB-4 neuroblastoma cell lines was found to be a mechanism of adaptation of these cells to hypoxia. An increase in acetylation of histones H3 and H4 is suggested to cause changes in the structure of chromatin that lead to activation of gene transcription. In addition, cultivation of tested neuroblastoma cells under hypoxic conditions changes expression of proteins of a transcription factor N-myc, which is essential for development of neuroblastomas. This transcription factor is also responsible for a metabolic adaptation of neuroblastoma cells, increases their aggressiveness and its expression leads to a worse prognosis of the disease. Inhibitors of histone deacetylases (HDAC) are suggested to be the promising agents exhibiting various anticancer effects. They can induce cell cycle arrest, differentiation or programmed cell death in sensitive tumors. In this study, the effect of one of inhibitors of HDACs, valproate, on expression of proteins of transcription factors N-myc and hypoxia inducible factor 1α (HIF-1α) was investigated. Valproate decreases protein levels of both transcription factors in...
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Role of signaling pathways and redox processes in cancer cell biology
Vališ, Karel ; Kovář, Jan (advisor) ; Anděra, Ladislav (referee) ; Kozubík, Alois (referee)
5 identifikovali VDAC2 protein jako možný transportér železa do nádorových buněk a tudíž možný cíl protinádorové terapie. Abstract Specific apoptosis induction in cancer cells represents promising way of anticancer therapy without damaging healthy tissues. Hence, search for new molecular targets capable of specific apoptosis triggering is highly challenging, mainly due to new and effective anti-cancer therapies development. Cancer cell metabolism (1) and mainly mitochondrial metabolism (2) seems to represent intriguing target. Mitochondria play essential role in life of the cell but on the other hand mitochondria activate cell death which is usually connected to increased ROS (reactive oxygen species) production. Contribution of this work is identification of vitamin E analogues as inhibitors of complex II and potent inductors of mitochondrial ROS in cancer cells. Additionally, we have demonstrated activation of conserved Hippo/Mst1 kinase in response to the vitamin E analogues which results in FoxO1 nuclear localization, NOXA gene transactivation, Bak protein activation, mitochondrial membrane permeabilisation and apoptosis induction. Next we searched for membrane proteins with increased expression in cancer cells exposed to iron deprivation. These proteins can play a role in iron metabolism of cancer...
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