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  • 1
    Keywords: APOPTOSIS ; CANCER ; THERAPY ; BIOLOGY ; PHOSPHORYLATION ; DEGRADATION ; sensitization ; THERAPIES
    Abstract: Resistance to apoptosis is one reason for the poor response of malignant brain tumors to therapy. The PPARgamma-modulating drug Troglitazone downregulates the anti-apoptotic FLIP protein and sensitizes glioblastoma cells to apoptosis induced by the death ligand TRAIL. To investigate the molecular basis of an experimental combination therapy for malignant gliomas with TRAIL and Troglitazone, we investigated the Troglitazone-induced signaling cascades and the expression of TRAIL receptors and FLIP in malignant gliomas. Troglitazone downregulated the FLIP protein through accelerated ubiquitin/proteasome-dependent degradation, which might be mediated by a Troglitazone-induced increase in reactive oxygen species. Moreover, Troglitazone induced the phosphorylation of the MAP kinase ERK1/2 as well as of the BAD protein. Inhibition of either PPARgamma or MEK1/2 blocked the Troglitazone-mediated phosphorylation of BAD and further increased the synergistic induction of glioma cell death by TRAIL and Troglitazone. Immunohistochemical analysis demonstrated that FLIP and TRAIL-R2 were significantly higher expressed in anaplastic (WHO grade III) than in diffuse (WHO grade II) gliomas. High FLIP and low TRAIL-R2 expression levels were associated with a poor prognosis of patients. Our findings warrant a further pre-clinical evaluation of an experimental anti-glioma therapy with TRAIL and Troglitazone, potentially in conjunction with a MAP kinase inhibitor.
    Type of Publication: Journal article published
    PubMed ID: 19158480
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  • 2
    Keywords: ANGIOGENESIS ; CANCER ; CELLS ; GROWTH ; IN-VITRO ; proliferation ; tumor ; TUMOR-CELLS ; CELL ; ENDOTHELIAL GROWTH-FACTOR ; Germany ; IN-VIVO ; MICROSCOPY ; MODEL ; THERAPY ; VITRO ; VIVO ; POPULATION ; GENE-EXPRESSION ; DIFFERENTIATION ; cytokines ; ACID ; TARGET ; DESIGN ; resistance ; EFFICACY ; STEM-CELLS ; PPAR-GAMMA ; RETINOIC ACID ; PHASE-II ; chemoresistance ; TRANS-RETINOIC ACID ; CYTOKINE ; ONCOLOGY ; secretion ; GLIOMA ; GLIOMA-CELLS ; MALIGNANT GLIOMAS ; TUMORIGENICITY ; MOTILITY ; GLIOBLASTOMA ; STEM ; TUMOR-INITIATING CELLS ; MARKER CD133
    Abstract: Purpose: Stem-like tumor cells comprise a highly tumorigenic and therapy-resistant tumor subpopulation, which is believed to substantially influence tumor initiation and therapy resistance in glioma. Currently, therapeutic, drug-induced differentiation is considered as a promising approach to eradicate this tumor-driving cell population; retinoic acid is well known as a potent modulator of differentiation and proliferation in normal stem cells. In glioma, knowledge about the efficacy of retinoic acid-induced differentiation to target the stem-like tumor cell pool could have therapeutic implications. Experimental Design: Stem-like glioma cells (SLGC) were differentiated with all-trans retinoic acid-containing medium to study the effect of differentiation on angiogenesis, invasive growth, as well as radioresistance and chemoresistance of SLGCs. In vivo effects were studied using live microscopy in a cranial window model. Results: Our data suggest that in vitro differentiation of SLGCs induces therapy-sensitizing effects, impairs the secretion of angiogenic cytokines, and disrupts SLGCs motility. Further, ex vivo differentiation reduces tumorigenicity of SLGCs. Finally, we show that all-trans retinoic acid treatment alone can induce antitumor effects in vivo. Conclusions: Altogether, these results highlight the potential of differentiation treatment to target the stem-like cell population in glioblastoma. Clin Cancer Res; 16(10); 2715-28. (C) 2010 AACR
    Type of Publication: Journal article published
    PubMed ID: 20442299
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  • 3
    Abstract: Cells dying by necrosis release the high-mobility group box 1 (HMGB1) protein, which has immunostimulatory effects. However, little is known about the direct actions of extracellular HMGB1 protein on cancer cells. Here, we show that recombinant human HMGB1 (rhHMGB1) exerts strong cytotoxic effects on malignant tumor cells. The rhHMGB1-induced cytotoxicity depends on the presence of mitochondria and leads to fast depletion of mitochondrial DNA, severe damage of the mitochondrial proteome by toxic malondialdehyde adducts, and formation of giant mitochondria. The formation of giant mitochondria is independent of direct nuclear signaling events, because giant mitochondria are also observed in cytoplasts lacking nuclei. Further, the reactive oxygen species scavenger N-acetylcysteine as well as c-Jun NH(2)-terminal kinase blockade inhibited the cytotoxic effect of rhHMGB1. Importantly, glioblastoma cells, but not normal astrocytes, were highly susceptible to rhHMGB1-induced cell death. Systemic treatment with rhHMGB1 results in significant growth inhibition of xenografted tumors in vivo. In summary, rhHMGB1 induces a distinct form of cell death in cancer cells, which differs from the known forms of apoptosis, autophagy, and senescence, possibly representing an important novel mechanism of specialized necrosis. Further, our findings suggest that rhHMGB1 may offer therapeutic applications in treatment of patients with malignant brain tumors.
    Type of Publication: Journal article published
    PubMed ID: 20959471
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  • 4
    Keywords: GENE-EXPRESSION ; DENDRITIC CELLS ; PROSTATE-CANCER ; CHROMATIN PROTEIN ; CYTOKINE ; LATE MEDIATOR ; Bcl-2 family proteins ; SYSTEMIC INFLAMMATION ; ANTICANCER CHEMOTHERAPY ; MOBILITY GROUP BOX-1
    Abstract: The HMGB1 protein has multiple functions in tumor biology and can act both as a transcription factor and as a cytokine. HMGB1 is released during cell death, and in our previous studies we demonstrated that HMGB1 induces a distinct, necrosis-like cell death in glioblastoma. In epithelial malignant tumors such as colorectal cancer (CRC), the HMGB1-dependent effects show cross-talk with apoptotic signal transduction. Treatment of CRC cells with low concentrations of recombinant HMGB1 results in dose-dependent cytotoxicity which is morphologically characterized by the formation of giant mitochondria and does not share features of apoptosis. HMGB1-triggered cell death is associated with intracellular ROS release, and overexpression of Bcl-2 blocks both the increase of ROS as well as HMGB1-dependent cell death. Importantly, treatment with recombinant HMGB1 or overexpression of endogenous HMGB1 strongly sensitizes CRC cells to the cytotoxic activity of the pro-apoptotic death ligand TRAIL as well as the small molecule Bcl-2 family inhibitor ABT-737. Moreover, treatment of CRC cells with TRAIL or ABT-737 induces a release of endogenous HMGB1 into the extracellular space, and preincubation with glycyrrhizin, an HMGB1 inhibitor, significantly inhibits induction of cell death by TRAIL and ABT-737, suggesting that HMGB1 functionally contributes to the execution of cell death triggered by pro-apoptotic agents. Finally, we investigated the expression of HMGB1 in human CRC tumor samples and found that loss of HMGB1 expression is associated with a more aggressive phenotype and a more advanced stage of disease in patients with CRC. Altogether, our findings demonstrate a functional link between cytotoxic signaling cascades triggered by HMGB1 and pro-apoptotic agents leading to an HMGB1-dependent sensitization to CRC cell death. Thus, a further evaluation of recombinant HMGB1 as part of an experimental combination treatment of CRC seems warranted.
    Type of Publication: Journal article published
    PubMed ID: 25434832
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  • 5
    Abstract: Targeting tumor glycolysis would hit the main energy source of cancer. We show that natural killer (NK) cells pursue this strategy by employing high mobility group box 1 (HMGB1) protein-a well-known proinflammatory cytokine-to specifically target glycolysis in cancer cells. This opens up new perspectives for cancer immunotherapy.
    Type of Publication: Journal article published
    PubMed ID: 27652323
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  • 6
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    Pathologe 37 (Suppl 2), 169-172 
    Abstract: The German Nobel Prize winner Otto Warburg discovered the importance of glycolysis in cancer cells in the 1920s. Nearly one century later the inhibition of tumor glycolysis in cancer cells could literally be the Achilles Heel in cancer therapy. Surprisingly, we could show that Natural Killer (NK) cells pursue this strategy. They employ specific metabolic weapons to eliminate cancer cells by targeting tumor glycolysis. In colon cancer cells a specifically modified form of high mobility group box 1 (HMGB1) protein released by NK cells induced a previously unknown form of cell death. This new link between the killing of cancer cells and the innate immune system opened up new perspectives for immunotherapy in oncology.
    Type of Publication: Journal article published
    PubMed ID: 27638530
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  • 7
    Keywords: brain ; PEPTIDE ; APOPTOSIS ; CANCER ; CELLS ; GROWTH ; IN-VITRO ; INHIBITOR ; INVASION ; tumor ; TUMOR-CELLS ; CELL ; Germany ; human ; IN-VIVO ; INHIBITION ; KINASE ; VITRO ; VIVO ; DEATH ; DISTINCT ; PROTEIN ; RNA ; TUMORS ; ACTIVATION ; BIOLOGY ; DOWN-REGULATION ; treatment ; CLEAVAGE ; ASSAY ; resistance ; CELL-DEATH ; INDUCED APOPTOSIS ; DECREASE ; STRESS ; RESECTION ; CANCER-CELLS ; MIGRATION ; STRATEGIES ; CONSTITUTIVE ACTIVATION ; CASPASE 8 ; CROSS-TALK ; CD95 ; CASPASE ; INHIBITORS ; signaling ; ONCOLOGY ; RE ; PATTERN ; BRAIN-TUMORS ; GLIOMA ; GLIOMA-CELLS ; MALIGNANT GLIOMAS ; CASPASE-8 ; ASSAYS ; cell death ; PROMOTION ; USA ; caspases ; focal adhesion kinase ; gelsolin ; cancer research ; in vivo ; MOTILITY ; GLIOBLASTOMA ; PROMOTES ; apoptotic ; caspase-3 ; block ; SMALL INTERFERING RNA ; SECONDARY GLIOBLASTOMAS ; CELLULAR-RESISTANCE ; RADIOCHEMOTHERAPY
    Abstract: Glioblastomas, the most malignant of all brain tumors, are characterized by cellular resistance to apoptosis and a highly invasive growth pattern. These factors contribute to the poor response of glioblastomas to radiochemotherapy and prevent their complete neurosurgical resection. However, the driving force behind the distinct motility of glioma cells is only partly understood. Here, we report that in the absence of cellular stress and proapoptotic stimuli, human glioblastoma cells exhibit a constitutive activation of caspases in vivo and in vitro. The inhibition of caspases by various peptide inhibitors decreases the migration of cells in scrape motility assays and the invasiveness of cells in spheroid assays. Similarly, specific small interfering RNA- or antisense-mediated down-regulation of caspase-3 and caspase-8 results in an inhibition of the migratory potential of glioma cells. The constitutive caspase-dependent motility of glioblastoma cells is independent of CD95 activation and it is not mediated by mitogen-activated protein/ extracellular signal-regulated kinase kinase signaling. The basal caspase activity is accompanied by a constant cleavage of the motility-associated gelsolin protein, which may contribute to the caspase-mediated promotion of migration and invasiveness in glioblastoma cells. Our results suggest that the administration of low doses of caspase inhibitors that block glioma cell motility without affecting the execution of apoptotic cell death may be exploited as a novel strategy for the treatment of glioblastomas
    Type of Publication: Journal article published
    PubMed ID: 18171980
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  • 8
    Keywords: CANCER ; CELLS ; EXPRESSION ; INVASION ; proliferation ; tumor ; TUMOR-CELLS ; carcinoma ; CELL ; Germany ; human ; INHIBITION ; LUNG ; COMMON ; lung cancer ; LUNG-CANCER ; HEPATOCELLULAR-CARCINOMA ; GENE-EXPRESSION ; PROTEIN ; PROTEINS ; LINES ; FAMILY ; TISSUES ; DYNAMICS ; CELL-LINES ; DOWN-REGULATION ; MEMBERS ; SEQUENCE ; TARGET ; LOCALIZATION ; MIGRATION ; MICROTUBULES ; MORPHOLOGY ; adenocarcinoma ; squamous cell carcinoma ; OVEREXPRESSION ; cell lines ; non-small cell lung cancer ; HUMAN BREAST-CANCER ; MATRIX ; CELL CARCINOMA ; FAMILIES ; cell proliferation ; USA ; MICROTUBULE DYNAMICS ; MOTILITY ; SQUAMOUS-CELL ; MALIGNANT PHENOTYPE ; therapeutic ; WELL ; CELL-LUNG-CANCER ; additive ; HUMAN HEPATOCARCINOGENESIS ; MYC EXPRESSION
    Abstract: Dynamic instability of the microtubule network modulates processes such as cell division and motility, as well as cellular morphology. Overexpression of the microtubule-destabilizing phosphoprotein stathmin is frequent in human malignancies and represents a promising therapeutic target. Although stathmin inhibition gives rise to antineoplastic effects, additional and functionally redundant microtubule-interacting proteins may attenuate the efficiency of this therapeutic approach. We have systematically analyzed the expression and potential protumorigenic effects of stathmin family members in human non-small cell lung cancer (NSCLC). Both stathmin and stathmin-like 3 (SCLIP) were overexpressed in adenocarcinoma as well as squamous cell carcinoma (SCC) tissues and induced tumor cell proliferation, migration, and matrix invasion in respective cell lines. Accordingly, reduced stathmin and SCLIP levels affected cell morphology and were associated with a less malignant phenotype. Combine inhibition of both factors caused additive effects on tumor cell motility, indicating partial functional redundancy. Because stathmin and SCLIP expression significantly correlated in NSCLC tissues, we searched for common upstream regulators and identified the far upstream sequence element-binding protein-1 (FBP-1) as a pivotal inducer of several stathmin family members. Our results indicate that the coordinated overexpression of microtubule-destabilizing factors by FBP-1 is a critical step to facilitate microtubule dynamics and subsequently increases proliferation and motility of tumor cells. [Cancer Res 2009;69(6):2234-43]
    Type of Publication: Journal article published
    PubMed ID: 19258502
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  • 9
    Keywords: Myocarditis ; Novel influenza A ; Swine flu ; H1N1
    Abstract: The main cause of death from novel (swine origin) influenza A/H1N1 infection is acute respiratory distress syndrome. Most fatal cases are immunocompromised patients or patients with a severe underlying disease. Here, we report a fatal case of acute interstitial myocarditis associated with novel influenza A/H1N1 infection in an immunocompetent young woman. A previously healthy 18-year-old woman experienced malaise, diarrhea, and fever for several days prior to a sudden collapse at home. Autopsy revealed a predominantly lymphocytic myocarditis in the absence of a significant respiratory tract infection. Infection with novel (swine origin) influenza A/H1N1 was confirmed by PCR analysis of blood as well as myocardial tissue. Influenza-caused diarrhea with consecutive hypokalemia potentially contributed to the fatal outcome of the myocarditis, characterized by ventricular fibrillation. In conclusion, sudden death by myocarditis may be a rare complication of novel influenza A/H1N1 infection in otherwise healthy individuals, even in the absence of significant respiratory tract infection.
    Type of Publication: Journal article published
    PubMed ID: 21234762
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  • 10
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    BIOspektrum 17 (4), 415-417 
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