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Cancer metabolism and its role in the sensitivity to ASNase of leukemic cells to L-asparaginase
Alquezar Artieda, Natividad ; Starková, Júlia (advisor) ; Procházka, Vít (referee) ; Truksa, Jaroslav (referee)
Cancer metabolism and its role in the sensitivity of leukemic cells to L- asparaginase ABSTRACT No ultimate treatment strategy exists for relapsed or non-responsive (15-20%) children with acute lymphoblastic leukemia (ALL). In this study, we aimed to elucidate the impact of metabolic rewiring in leukemic cells on poor therapy response and the emergence of resistance. This dissertation focuses on l-asparaginase (ASNase), a crucial chemotherapeutic agent and its effect on leukemia, using models of leukemic cell lines and primary cells of ALL patients. Cell metabolism was assessed by measuring metabolic pathways and nutrient influx using a Seahorse analyzer and stable isotope tracing. Main findings of the study demonstrated that the ASNase- therapy response was mitigated by the activity of the mechanistic target of rapamycin (mTOR)- regulated biosynthetic pathways. This phenomenon was induced by the bone marrow environment, which enabled the activation of the resistant mechanism in leukemic cells. We next found a correlation between the following metabolic features and lower sensitivity to ASNase: low ATP- linked respiration, high mitochondrial membrane potential and high glycolytic flux before therapy. The latter was shown to have prognostic implications. Moreover, high glycolytic flux was detected in T-ALL...
The role of iron in the regulation of proteins connected with tamoxifen-resistance
Potomová, Petra ; Truksa, Jaroslav (advisor) ; Balušíková, Kamila (referee)
Cancer cells are highly dependent on nutrient uptake to sustain their increased proliferation, one of these nutrients being iron. In recent years, a heightened dependency on iron was observed in cancer cells, allowing for the proper function of numerous enzymes, DNA synthesis and mitochondrial respiration. Here, we further delve into the iron metabolism of malignant cells, attempting to understand the differences between tamoxifen-sensitive and resistant (Tam5R) ones using two breast cancer cell lines of luminal A origin, MCF7 and T47D. These cells show numerous changes in iron homeostasis and iron-dependent mechanisms. Based on alterations in proteomes of Tam5R cell lines, we focused on iron regulation of proteins that are deregulated in tamoxifen resistance - assessing their regulation on transcriptional (mRNA) and post-transcriptional level (protein) as well as comparing their responsiveness to their sensitive parental cell line. We assessed two main types of regulation - iron-responsive element interaction with iron-regulatory proteins (IRE-IRP pathway) and tristetraprolin (TTP) driven mRNA degradation via AU-rich elements (ARE). Using iron loading and chelation, we challenged the cells - confirming the known IRE-IRP regulation of ferritin heavy chain (FTH), transferrin receptor 1 (TfR1),...
Inhibition of P-glycoprotein-mediated multidrug resistance and STAT3 signaling pathway through polymeric conjugates bearing protease inhibitor derivatives
Starenko, Daniil ; Kovář, Marek (advisor) ; Truksa, Jaroslav (referee)
Tumor cells expressing high levels of some ABC transporters (mainly P-glycoprotein) can become resistant to many structurally and functionally different drugs. Such multidrug resistance can be a significant barrier for a successful chemotherapy of malignant diseases. There is a considerable amount of small-molecular-weight compounds capable of potent inhibition of P-glycoprotein, but none of them are approved for the clinical use. STAT3 is a transcription factor important for many physiological processes, but its constitutive activation may lead to the malignant transformation and chemotherapy resistance in tumor cells. This molecule is thus potential target for anticancer drugs. The inhibition of STAT3 signaling should lead to lower cancer cell proliferation and their increased susceptibility to induction of apoptosis. Considerable attention is given to increase the effectiveness and to lower the adverse effects of conventional cytostatic agents via using nanomaterials and drug delivery systems in the research of new cancer therapy approaches. Polymeric carriers based on N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers are promising candidates in this field. The main aim of this diploma thesis was to evaluate the effectiveness of several HIV protease inhibitor (ritonavir, lopinavir, indinavir,...
Molecular mechanisms of checkpoint signalling and termination
Benada, Jan ; Macůrek, Libor (advisor) ; Brábek, Jan (referee) ; Truksa, Jaroslav (referee)
Cells employ an extensive signalling network to protect their genome integrity, termed DNA damage response (DDR). The DDR can trigger cell cycle checkpoints which prevent cell cycle progression and allow repair of DNA damage. The failures in these safeguarding mechanism are represented by serious human malignancies, most predominantly by cancer development. This work aims to contribute to the understanding of how do the cells negatively regulate DDR and cell cycle checkpoint signalling. We focused mainly on Wip1 (PPM1D) phosphatase, which is a major negative regulator of DDR and is indispensable for checkpoint recovery. Firstly, we have shown that Wip1 is degraded during mitosis in APC-Cdc20 dependent manner. Moreover, Wip1 is phosphorylated at multiple residues during mitosis, resulting in inhibition of its enzymatic activity. We suggest that the abrogation of Wip1 activity enables cells to react adequately even to low levels of DNA damage encountered during unperturbed mitosis. In the following publication, we have investigated why the mitotic cells trigger only early events of DDR and do not proceed to the recruitment of DNA repair factors such as 53BP1. We showed that 53BP1 is phosphorylated within its ubiquitination-dependent recruitment domain by CDK1 and Plk1. These phosphorylations prevents...
Mitochondria as a target for anti-cancer therapy
Monschizadeh Tehrany, Shahin ; Truksa, Jaroslav (advisor) ; Kalous, Martin (referee)
Cancer is a complex disease that is characteristic by its heterogeneity in forms and symptoms. This diversity is caused by various mutations in oncogenes and tumor suppressor genes, which then makes cancer a very unclear and indistinct target. However numerous neoplastic characteristics are linked to the functions of mitochondria. This then makes mitochondria a center of interest of cancer research. Many cancer cells show the switch to the metabolism of aerobic glycolysis witch is characteristic by the increased glucose uptake, increased activity of biosynthetic pathways and lower oxidative capacity of mitochondria. Another mitochondria-linked modification is the increased production of reactive oxygen species in cancer cells, which are a source of new mutations and enhance cell proliferation. An increased transmembrane potential on the inner mitochondrial membrane is another very common feature that also promotes cell division and directly correlates with cancer malignancy. In this context a group of antitumor drugs called mitocans was discovered, that acts on the altered mitochondria of tumor cells. The activity of mitocans is ranging from the restoration of the function of pro-apoptotic molecules to the enforced cell death caused by oxidative damage done to the mitochondria of cancer cells....
Cell death as a result of iron-induced cellular damage
Běhounek, Matěj ; Balušíková, Kamila (advisor) ; Truksa, Jaroslav (referee)
Iron is an essential trace element for almost all living organisms. Iron overload in cells and tissues, however, leads to their disruption. Most oftenly damaged are parenchymatic organs such as the liver, pancreas and heart. The aim of this thesis was to create cellular in vitro models for the investigation of effects of excess iron on hepatocytes and pancreatic beta cells and on these models to investigate cellular processes which lead to cellular damage during iron overload. We focused on examining the presence of oxidative and endoplasmic reticulum stress and the activation of apoptotic cell death. For our experiments, we used HEP-G2 cell line which represents human hepatocytes and NES2Y cell line which represents human pancreatic beta cells. To study the mechanisms of cellular damage during iron overload, we used two approaches by which we observed both acute and long-term effects of high levels of iron on damage of the tested cell lines. When studying the acute effect of excess iron on the cells, we applied high doses of iron (using 15 mM ferric citrate in medium) that led to the activation of cell death in hours. Long-term effects of iron overload were tested on cells regularly cultivated in the presence of 50 μM and 100 μM ferric citrate over a period of several months. Iron concentrations...
The role of autophagy in apoptosis induction by fatty acids in pancreatic beta cells.
Žigová, Ivana ; Němcová, Vlasta (advisor) ; Truksa, Jaroslav (referee)
Type 2 diabetes mellitus represents a metabolic disease reaching epidemic dimensions in the 21st century. Fatty acid-induced apoptosis of pancreatic β-cells significantly contributes to its pathogenesis. Saturated fatty acids (FAs) are strongly cytotoxic for β-cells, whereas unsaturated FAs are well tolerable by β-cells, they are even able to inhibit proapoptotic effects of saturated FAs when co-incubated. According to recent studies, FAs-induced apoptosis in pancreatic β-cells is partly regulated by autophagy, a catabolic process involved in the degradation and recyclation of cell components in lysosomes. The aim of this diploma thesis was to contribute to the clarification of the role of autophagy in FAs-induced apoptosis regulation. We induced apoptosis in human pancreatic β- cell line NES2Y by 1 mM stearic acid (SA) and inhibited it with 0.2 mM oleic acid (OA) co- incubated with SA. We revealed, that the saturated SA used in apoptosis-inducing concentration simultaneously inhibits the autophagic flux in pancreatic NES2Y cell line. When SA is co- incubated with unsaturated OA in concentration sufficient for inhibition of proapoptotic effect of SA, OA is also able to inhibit the block of autophagy induced by the effect of SA. Application of unsaturated OA alone in this concentration did not...
Analyzing the role of the p130Cas SH3 domain in p130Cas-mediated signaling
Gemperle, Jakub ; Rösel, Daniel (advisor) ; Vomastek, Tomáš (referee) ; Truksa, Jaroslav (referee)
The adaptor protein p130Cas (CAS, BCAR1) represents a nodal signaling platform for integrin and growth factor receptor signaling, and influences normal development and tissue homeostasis. Its altered expression drives many pathological conditions including tumor growth, metastasis and drug resistance in many cancer types. How p130Cas contributes to many of these pathologies is still poorly understood. Therefore, the overall aim of my PhD work was to provide new insights to p130Cas signaling and its regulation. The SH3 domain is indispensable for p130Cas signaling, but the ligand binding characteristics of the p130Cas SH3 domain, and the structural determinants of its regulation were not well understood. To be able to study various aspects of p130Cas signaling we identified an atypical binding motif in p130Cas SH3 domain by establishing collaborations with Dr Veverka (Structural biology) and Dr Lepšík (Computational biochemistry; Academy of Sciences, CZ) which gave new insight into this binding interface. Through these collaborations I generated chimeras of p130Cas SH3 domain with its ligands for structural NMR analysis and learned how to visualize and analyze structures. Furthermore, my work expanded our knowledge of p130Cas SH3 ligand binding regulation and led to a novel model of Src-p130Cas- FAK...
Charakterizace vlivu senescence na indukci a regulaci smrti nádorových buněk
Nováková, Gita ; Anděra, Ladislav (advisor) ; Truksa, Jaroslav (referee)
4 Abstract Senescence is a specific cell state distinquished by cessation of cell division and proliferation and changes in gene expression. Normal cells enter senescence after distinct number of cell divisions or in case of an unrepairable damage. Senescence in cancer cells can be induced by subliminal stress as sublethal treatment with certain drugs. Senescent cancer cells persist in the tissue and may secrete a number of factors and nutrients affecting surrounding cells. Senescence can thus change the response of cancer cells to various apoptogens during cancer therapy. In this study, we focused on the elucidation of presumed differences between normal proliferating and senescent cancer cells in their response to selected apoptogens. Implementing bromodeoxyuridine (BrdU)-mediated replication stress in cancer cells derived from pancreatic (PANC-1) or mesothelioma (H28) tumors, we efficiently forced these cells to acquire senescent phenotype. We document that these senescent cells gain higher resistance to combined TRAIL and homoharringtonine (HHT) treatment and enhance sensitivity to other apoptogens such as FasL, camptothecin and mVES. These cells also showed increased expression of anti-apoptotic protein c-FLIP in senescent cells and changes in the expression of some Bcl-2 family proteins....
Iron metabolism in cancer cells
Beranová, Lea Marie ; Truksa, Jaroslav (advisor) ; Čermák, Vladimír (referee)
1Abstract: Cancer is one of the major causes of death in the present world. As the research of this disease has progressed, the attention of some scientists has been focused on a metabolism of iron and how it can be used to fight these rapidly proliferating invasive cells and stop their spreading. This work should serve as a brief review of iron metabolic processes from the iron absorption from dietary resources and recycled cell iron, to its usage in heme- or Fe/S clusters-proteins and storage in a form of ferritin, while highlighting the points that differ in cancer cells. It also gives a modest overview on the regulatory pathways of iron uptake and use, and mentions iron metabolism disorders such as iron-depletion and overload. Simultaneously it is denoting possible differences that could be targeted in tumor treatment, and, at least but not last, the perspectives and future work that could bring a new methods and approaches to this matter. Keywords: iron metabolism, iron, cancer, hepcidin

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