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The study of the influence of vitamin E analogues on malignant mesothelioma
Kovářová, Jaromíra ; Neužil, Jiří (advisor) ; Kozubík, Alois (referee) ; Vítek, Libor (referee)
Cancer is a leading cause of death in the western world and is increasing in frequency world-wide. Although diagnosis, treatment and therapeutic approaches to cancer have improved, many types of cancer are still lethal due to the lack of radical treatment. One of the fatal neoplastic disease types with poor prognosis is represented by malignant mesothelioma (MM). MM is characterised by very high mortality rate and limited therapeutic options. The etiology of the disease is mainly associated with exposure to asbestos fibres. The incidence of MM is increasing in many countries. The search for novel molecular targets, anti-cancer strategies and drugs, which would considerably improve the treatment is of great importance. Certain new drugs, especially those with specific molecular targets, show high selectivity in their action to cancer cells, and have considerably increased the cure rate in some types of cancer. Mitochondria have recently emerged as a very promising target for anti-cancer agents. A group of compounds with anti-cancer activity that induce apoptosis by way of mitochondrial destabilisation, termed 'mitocans', have been a recent focus of research. Several mitocans have been shown to selectively induce apoptosis in cancer cells and suppress the growth of many types of carcinomas in...
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The role of Hippo Signalling pathway in tumor cell metabolism
Lettlová, Sandra ; Stiborová, Marie (advisor) ; Dračínská, Helena (referee)
Vitamine E analogues α-tocopheryl succinate (α-TOS) and mitochondrially targeted vitamine E succinate (MitoVES) are anti-cancer agents from the group of "mitocans", the compounds acting via mitochondria which present a promising invariant target for cancer cell therapy. α-TOS and MitoVES induce apoptosis selectively in various cancer cell types involving generation of reactive oxygen species (ROS). Generated superoxid anion radicals in response to α-TOS and MitoVES are believed to be converted into hydrogen peroxide that is known to activate Mammalian sterile 20-like kinase (Mst1), the central component of Hippo signalling pathway, that presents an universal size control mechanism in all metazoans and its deregulation is linked to tumourigenesis. MitoVES and α-TOS were both reported to activate Mst1 that phosphorylates Forkhead box O1 (FoxO1) transcription factor resulting in its transport to nucleus where induce the expression of pro-apoptotic genes, including NOXA, and thus promote apoptosis. The target of Hippo signalling pathway is transcriptional co- activator Yes-associated protein (Yap) which was found in Drosophila melanogaster to regulate the expression of transcription factor c-Myc which is known as the most prominent human oncogene. This thesis focused on involvement of Hippo signalling...
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Úloha Mst1 / FoxO dráhy při indukci apoptosy
Lettlová, Sandra ; Bezouška, Karel (advisor) ; Liberda, Jiří (referee)
Vitamin E analogue -tocopheryl succinate (-TOS) from the group of mitocans, the drugs targeting mitochondria, is a selective inducer of apoptosis in various cancer cell types, which involves the accumulation of reactive oxygen species (ROS). It was found that ROS generation causes p53-independent upregulation of the pro-apoptotic protein Noxa that induces apoptosis by displacement of the BH3-only protein Bak from its inactive complex with the anti-apoptotic protein Mcl-1 to form a pore in outer mitochondrial membrane. Current research has demonstrated that generation of ROS causes activation of Mst1, a component of the Hippo pathway that presents a universal size-control mechanism in all metazoans, whose deregulation is linked to tumorigenesis. Treatment of Jurkat cells with - TOS revealed that activated Mst1 kinase phosphorylates the Forkhead box O1 (FoxO1) transcription factor that then translocates to the nucleus and activates transcription of genes important for apoptosis induction, including NOXA. This explains the p53 independent apoptosis induction and presents Mst1-FoxO1-Noxa as a new pathway involved in the process. Current research has also documented that activated Mst1 kinase controls the expression of the c-MYC oncogene and its target genes, whose products are involved in glucose...
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