Cílem řešitelského kolektivu je snaha přispět k vyhodnocení tzv. metastatického potenciálu a to zejména u časných forem nádorů kolorekta. Projekt připraven na základě úzké spolupráce mezi činnosti chirurga, patologa, onkologa a molekulárního biologa (Ústav exp.biologie Přírodovědecké fakulty MU); The aim of the investigator team is to contribute to the evaluation of the so- called metastatic potential mainly in early forms of colorectal cancer. The project is prepared upon direct cooperation between surgeon, pathologist, oncologist and mollecular biologist (Department of Experimental Biology, Faculty of Natural Sciences, MU Brno)

• MeSH
• biopsie sentinelové lymfatické uzliny MeSH
• imunohistochemie MeSH
• kolorektální nádory diagnóza   MeSH
• metastázy nádorů diagnóza   MeSH
• nádorové biomarkery analýza   MeSH
• onkogenní proteiny v-myb analýza   MeSH
• protoonkogenní proteiny c-myb analýza   MeSH

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• gastroenterologie
• onkologie
• biologie
• NLK Publikační typ
• závěrečné zprávy o řešení grantu IGA MZ ČR

• Publikační typ
• abstrakt z konference MeSH

The c-Myb transcription factor is important for maintenance of immature cells of many tissues including colon epithelium. Overexpression of c-Myb occurring in colorectal carcinomas (CRC) as well as in other cancers often marks poor prognosis. However, the molecular mechanism explaining how c-Myb contributes to progression of CRC has not been fully elucidated. To address this point, we investigated the way how c-Myb affects sensitivity of CRC cells to anticancer drugs. Using CRC cell lines expressing exogenous c-myb we show that c-Myb protects CRC cells from the cisplatin-, oxaliplatin-, and doxorubicin-induced apoptosis, elevates reactive oxygen species via up-regulation of NOX1, and sustains the pro-survival p38 MAPK pathway. Using pharmacological inhibitors and gene silencing of p38 and NOX1 we found that these proteins are essential for the protective effect of c-Myb and that NOX1 acts upstream of p38 activation. In addition, our result suggests that transcription of NOX1 is directly controlled by c-Myb and these genes are strongly co-expressed in human tumor tissue of CRC patients. The novel c-Myb/NOX1/p38 signaling axis that protects CRC cells from chemotherapy described in this study could provide a new base for design of future therapies of CRC.

• MeSH
• aktivace enzymů účinky léků   MeSH
• apoptóza účinky léků   MeSH
• cisplatina farmakologie   MeSH
• doxorubicin farmakologie   MeSH
• kolorektální nádory genetika   patologie   MeSH
• lidé MeSH
• messenger RNA genetika   metabolismus   MeSH
• mitogenem aktivované proteinkinasy p38 genetika   metabolismus   MeSH
• myši MeSH
• NADH, NADPH oxidoreduktasy genetika   metabolismus   MeSH
• nádorové buněčné linie MeSH
• NADPH-oxidasy genetika   metabolismus   MeSH
• organoplatinové sloučeniny farmakologie   MeSH
• oxidační stres účinky léků   MeSH
• promotorové oblasti (genetika) genetika   MeSH
• protoonkogenní proteiny c-myb metabolismus   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• regulace genové exprese u nádorů * účinky léků   MeSH
• sekvence nukleotidů MeSH
• upregulace účinky léků   MeSH
• vazebná místa MeSH
• viabilita buněk MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The MYB gene codes for the c-Myb transcription factor maintaining proliferation of colon epithelial progenitors, thus controlling colon development and homeostasis. This gene is overexpressed in early phases of colorectal cancer (CRC) tumorigenesis. The aim of this study was to examine the expression of c-Myb in CRC tissue samples both at the messenger RNA (mRNA) and protein levels and to evaluate their associations with clinicopathological characteristics in a group of 108 CRC patients. Statistically significant negative association was found between the frequency of the c-Myb-positive tumor cells assessed by immunohistochemistry and the presence of distant metastases (p < 0.01) but not tumor differentiation, tumor stage, lymph node involvement, vascular invasion, tumor localization, age, and gender of the patients. Although the c-Myb protein level in the tumor tissue correlated with its mRNA level, no significant association between MYB mRNA and any clinicopathological characteristics was observed. We conclude that albeit overexpression of c-Myb is considered as an important factor contributing to early phases of CRC tumorigenesis, it may later have negative effect on tumor cell dissemination as observed recently in breast cancer as well. Further studies are required to explain the role of c-Myb during formation of CRC distant metastases.

• MeSH
• adenokarcinom genetika   sekundární   MeSH
• buněčná diferenciace MeSH
• dospělí MeSH
• down regulace MeSH
• geny myb * MeSH
• invazivní růst nádoru MeSH
• kolorektální nádory genetika   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lymfatické metastázy MeSH
• messenger RNA biosyntéza   MeSH
• nádorové proteiny biosyntéza   genetika   MeSH
• protoonkogenní proteiny c-myb biosyntéza   genetika   MeSH
• regulace genové exprese u nádorů MeSH
• RNA nádorová biosyntéza   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Cathepsin D (CD), a ubiquitously expressed lysosomal aspartic protease, is upregulated in human breast carcinoma and many other tumor types. CD has been repeatedly reported to act as key mediator of apoptosis induced by various chemotherapeutics. However, there is still controversy over the role of enzymatic/proteolytic versus protein-protein interaction activities of CD in apoptotic signaling. The elucidation of molecular mechanism responsible for the effect of CD in the chemotherapy-induced cell death is crucial for development of an appropriate strategy to target this protease in cancer treatment. Therefore, the objective of this study was to investigate the molecular mechanism behind the CD-mediated regulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cell death. For this purpose, MDA-MB-231 breast carcinoma cells with an increased level of wt CD (CD) or mutant enzymatically inactive CD (ΔCD) were subjected to TRAIL and the frequency of apoptosis was determined. Our results show that CD facilitates the TRAIL-induced apoptosis of MDA-MB-231 breast cancer cells in enzymatic activity-dependent manner. Moreover, the importance of endosomal/lysosomal acidification in this process was documented. Analysis of the potential substrates specifically cleaved by CD during the TRAIL-induced apoptosis confirmed caspase-8 and Bid proteins as the CD targets. Moreover, in search for protein regulators of apoptosis that can be cleaved by CD at physiologically relevant pH, we identified the Bcl-2 protein as a suitable candidate. The modulatory role of CD in cell response to TRAIL was also confirmed in another breast cancer cell line SKBR3. These experiments identified the CD enzymatic activity as a new factor affecting sensitivity of breast cancer cells to TRAIL.

• MeSH
• adenokarcinom enzymologie   patologie   MeSH
• aktivace enzymů MeSH
• apoptóza účinky léků   MeSH
• chemorezistence MeSH
• endozomy metabolismus   MeSH
• kaspasa 8 metabolismus   MeSH
• kathepsin D antagonisté a inhibitory   genetika   fyziologie   MeSH
• koncentrace vodíkových iontů MeSH
• lidé MeSH
• lyzozomy metabolismus   MeSH
• malá interferující RNA genetika   MeSH
• nádorové buněčné linie MeSH
• nádorové proteiny antagonisté a inhibitory   genetika   fyziologie   MeSH
• nádory prsu enzymologie   patologie   MeSH
• protein Bid metabolismus   MeSH
• protein TRAIL farmakologie   MeSH
• protoonkogenní proteiny c-bcl-2 metabolismus   MeSH
• rekombinantní proteiny metabolismus   farmakologie   MeSH
• RNA interference MeSH
• transfekce MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

• Publikační typ
• abstrakt z konference MeSH

Wedelolactone, a plant coumestan, was shown to act as anti-cancer agent for breast and prostate carcinomas in vitro and in vivo targeting multiple cellular proteins including androgen receptors, 5-lipoxygenase and topoisomerase IIα. It is cytotoxic to breast, prostate, pituitary and myeloma cancer cell lines in vitro at μM concentrations. In this study, however, a novel biological activity of nM dose of wedelolactone was demonstrated. Wedelolactone acts as agonist of estrogen receptors (ER) α and β as demonstrated by transactivation of estrogen response element (ERE) in cells transiently expressing either ERα or ERβ and by molecular docking of this coumestan into ligand binding pocket of both ERα and ERβ. In breast cancer cells, wedelolactone stimulates growth of estrogen receptor-positive cells, expression of estrogen-responsive genes and activates rapid non-genomic estrogen signalling. All these effects can be inhibited by pretreatment with pure ER antagonist ICI 182,780 and they are not observed in ER-negative breast cancer cells. We conclude that wedelolactone acts as phytoestrogen in breast cancer cells by stimulating ER genomic and non-genomic signalling pathways.

• MeSH
• aktivace transkripce genetika   MeSH
• alfa receptor estrogenů metabolismus   MeSH
• antagonisté estrogenového receptoru farmakologie   MeSH
• beta receptor estrogenů metabolismus   MeSH
• estradiol analogy a deriváty   farmakologie   MeSH
• estrogeny farmakologie   MeSH
• HEK293 buňky MeSH
• kumariny farmakologie   MeSH
• lidé MeSH
• MFC-7 buňky MeSH
• nádorové buněčné linie MeSH
• nádory prsu farmakoterapie   MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky farmakologie   MeSH
• responzivní elementy genetika   MeSH
• signální transdukce účinky léků   MeSH
• simulace molekulového dockingu MeSH
• transkripční faktor AP-1 metabolismus   MeSH
• vazebná místa účinky léků   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

SCOPE: The major alimentary sources for the plasma membrane lipid sphingomyelin (SM) are dairy products, eggs, and meat. We recently reported that the SM metabolite ceramide induces cathepsin D mediated apoptosis in murine intestinal epithelial cells (IECs) and increases inflammation in acute colitis. We investigated the impact of SM and phosphatidylcholine on apoptosis in human IECs and point out BH3-interacting death agonist (BID) as link between cathepsin D and apoptosis. METHODS AND RESULTS: HT-29 and isolated human IECs were stimulated with SM or phosphatidylcholine. SM treatment resulted in increased apoptosis. Phosphatidylcholine showed contrary effects. Western revealed higher amounts of cathepsin D and BID activation upon lipid stimulation. Western blotting revealed BID activation through SM in both an induced and a spontaneous mouse model of colitis. CONCLUSION: Dietary phospholipids may induce or abolish apoptosis in IECs and seem to play a role in the pathogenesis of inflammatory bowel diseases. This nutritional factor might be considered when evaluating the pathogenesis of inflammatory bowel diseases. Effects of SMase- and SM treatment on inflammation in dextran sulfate sodium induced animal models of colitis and in vitro experiments are discussed as controversial. Variable sources of SM, feeding techniques, and mouse strains might play a role.Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

• MeSH
• adhezní spoje MeSH
• apoptóza * účinky léků   MeSH
• buněčná smrt účinky léků   MeSH
• buňky HT-29 účinky léků   MeSH
• ceramidy metabolismus   MeSH
• epitelové buňky * patologie   účinky léků   MeSH
• fosfatidylcholiny farmakologie   metabolismus   MeSH
• kathepsin D metabolismus   MeSH
• kolitida metabolismus   patologie   MeSH
• kultivované buňky MeSH
• lidé MeSH
• liposomy farmakologie   MeSH
• myši inbrední C57BL MeSH
• potravní doplňky MeSH
• protein Bid metabolismus   MeSH
• sfingomyelinfosfodiesterasa metabolismus   MeSH
• sfingomyeliny farmakologie   metabolismus   MeSH
• střeva * cytologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• zvířata MeSH

Natural products are often used in drug development due to their ability to form unique and diverse chemical structures. Coumestans are polycyclic aromatic plant secondary metabolites containing a coumestan moiety, which consists of a benzoxole fused to a chromen-2-one to form 1-Benzoxolo[3,2-c]chromen-6-one. These natural compounds are known for large number of biological activities. Many of their biological effects can be attributed to their action as phytoestrogens and polyphenols. In the last decade, anticancer effects of these compounds have been described in vitro but there is only limited number of studies based on models in vivo. More information concerning their in vivo bioavailability, stability, metabolism, toxicity, estrogenicity, cellular targets and drug interactions is therefore needed to proceed further to clinical studies. This review focuses on coumestans exhibiting anticancer properties and summarizes mechanisms of their toxicity to cancer cells. Moreover, the possible role of coumestans in cancer prevention is discussed.

• MeSH
• antikarcinogenní látky chemie   metabolismus   terapeutické užití   MeSH
• fytoestrogeny metabolismus   MeSH
• fytogenní protinádorové látky chemie   metabolismus   terapeutické užití   MeSH
• kumariny chemie   metabolismus   terapeutické užití   MeSH
• lidé MeSH
• nádory farmakoterapie   prevence a kontrola   MeSH
• rostliny chemie   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

BACKGROUND: Resistance of cancer cells to chemotherapeutic agents is a major cause of treatment failure in patients with cancer. The drug resistance of tumor cells can be significantly modified by specific features of tumor microenvironment, such as oxygen depletion (hypoxia), glucose/energy deprivation and acidosis. METHODS: The effects of acidic tumor-like microenvironment on cytotoxicity of antabuse (disulfiram, DSF)/Cu(2+) complexes to MCF-7 breast carcinoma and HT-29 colon carcinoma cells were studied. RESULTS: We show that acidic pH significantly potentiates toxicity of DSF/Cu(2+) complex to breast and colon cancer cells. This phenomenon is associated with changes in cell metabolism, altered Akt kinase and NFκB activity and increased reactive oxygen species production. CONCLUSION: Specific pH of tumor microenvironment enhances cytotoxicity of DSF/Cu(2+) to breast and colon cancer cells.

• MeSH
• buňky HT-29 MeSH
• disulfiram chemie   MeSH
• fosforylace MeSH
• komplexní sloučeniny chemická syntéza   chemie   toxicita   MeSH
• koncentrace vodíkových iontů MeSH
• lidé MeSH
• měď chemie   MeSH
• MFC-7 buňky MeSH
• nádorové mikroprostředí účinky léků   MeSH
• nádory prsu metabolismus   patologie   MeSH
• nádory tračníku metabolismus   patologie   MeSH
• NF-kappa B metabolismus   MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky chemická syntéza   chemie   toxicita   MeSH
• protoonkogenní proteiny c-akt metabolismus   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH