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  • 1
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    German Medical Science; Düsseldorf, Köln
    In:  27. Deutscher Krebskongress; 20060322-20060326; Berlin; DOCPO269 /20060320/
    Publication Date: 2006-04-21
    Keywords: ddc: 610
    Language: English
    Type: conferenceObject
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  • 2
    Keywords: SYSTEM ; CANCER ; APOPTOSIS ; THERAPY ; INDUCTION ; treatment ; CANCER-THERAPY ; TRAIL ; function ; CANCER-TREATMENT ; cancer therapy
    Type of Publication: Book chapter
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  • 3
    Keywords: RECEPTOR ; APOPTOSIS ; CELLS ; INHIBITOR ; tumor ; TUMOR-CELLS ; carcinoma ; Germany ; human ; IN-VIVO ; INHIBITION ; DEATH ; HEPATOCELLULAR-CARCINOMA ; PROTEIN ; PROTEINS ; RNA ; LINES ; MICE ; TRANSDUCTION ; NF-KAPPA-B ; COMPLEX ; COMPLEXES ; MECHANISM ; CONTRAST ; hepatocytes ; CELL-LINES ; signal transduction ; SUPPRESSION ; 5-FLUOROURACIL ; ALPHA ; hepatocellular carcinoma ; resistance ; CARCINOMA CELLS ; EFFICACY ; SIGNAL-TRANSDUCTION ; LINE ; CANCER-CELLS ; CARCINOMA-CELLS ; KAPPA-B ; RECEPTORS ; FLOW-CYTOMETRY ; cell lines ; PROTEASOME ; TRAIL ; SIGNALING COMPLEX ; HUMAN HEPATOCYTES ; TRAIL-INDUCED APOPTOSIS ; APOPTOSIS-INDUCING LIGAND ; CASPASE-8 ACTIVATION ; INHIBITORS ; signaling ; RE ; INTERFERENCE ; CASPASE-8 ; MEDIATED APOPTOSIS ; TUMORICIDAL ACTIVITY ; interaction ; SIGNALING COMPLEXES ; CLINICAL-RELEVANCE ; carcinoma cell ; death receptor
    Abstract: TRAIL exhibits potent anti-tumor activity on systemic administration in mice. Because of its proven in vivo efficacy, TRAIL may serve as a novel anti-neoplastic drug. However, approximately half of the tumor cell lines tested so far are TRAIL resistant, and potential toxic side effects of certain recombinant forms of TRAIL on human hepatocytes have been described. Pretreatment with the proteasome inhibitor MG132 and PS-341 rendered TRAIL-resistant hepatocellular carcinoma (HCC) cell lines but not primary human hepatocytes sensitive for TRAIL-induced apoptosis. We investigated the different levels of possible MG132-induced interference with resistance to apoptotic signal transduction. Although proteasome inhibition efficiently suppressed nuclear factor-kappaB (NF-kappa B) activity, specific suppression of NF-kappa B by mut kappa B alpha failed to sensitize TRAIL-resistant cell lines for TRAIL-induced apoptosis. In contrast to the previously reported mechanism of sensitization by 5-fluorouracil (5-FU), cellular FLICE-inhibitory protein (cFLIP)(L) and cFLIP(S) were markedly upregulated in the TRAIL death inducing signaling complex (DISC) by proteasome inhibitor pretreatment. Compared with 5-FU pretreatment, caspase-8 was more efficiently recruited to the DISC in MG132 pretreated cells despite the presence of fewer death receptors and more cFLIP in the DISC., But downregulation of cFLIP by short interference RNA (siRNA) further sensitized the HCC cell lines. In conclusion, these results show that otherwise chemotherapy-resistant tumor cells can be sensitized for TRAIL-induced apoptosis at the DISC level in the presence of high levels of cFLIP, which suggests the existence of an additional factor that modulates the interaction of FADD and the TRAIL death receptors. Of clinical relevance, proteasome inhibitors sensitize HCC cells but not primary human hepatocytes for TRAIL-induced apoptosis
    Type of Publication: Journal article published
    PubMed ID: 16037944
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  • 4
    Keywords: RECEPTOR ; APOPTOSIS ; CELLS ; EXPRESSION ; carcinoma ; CELL ; Germany ; IN-VIVO ; INHIBITION ; PATHWAY ; DEATH ; GENE ; PROTEIN ; LINES ; ACTIVATION ; LIGAND ; DNA ; INFECTION ; REDUCTION ; DOMAIN ; CARCINOGENESIS ; INDUCTION ; T cells ; T-CELLS ; CELL-LINES ; CELL-LINE ; LYMPHOCYTES ; MITOCHONDRIA ; STOMACH ; RECEPTORS ; TRAIL ; REGULATOR ; inflammation ; FAS ; methods ; IMMUNE PRIVILEGE ; leukaemia ; death receptor ; INHIBIT ; Helicobacter pylori ; GASTRIC EPITHELIAL APOPTOSIS ; INFILTRATING MUCOSAL LYMPHOCYTES ; VACUOLATING CYTOTOXIN
    Abstract: Background Chronic infection with Helicobacter pylori is related to the pathogenesis of the noncardia carcinoma of the stomach. In this study we investigated the mechanisms of H. pylori-induced apoptosis in T lymphocytes, which could explain a mechanism of immune evasion facilitating chronic inflammation of the mucosa and gastric carcinogenesis. Materials and methods The supernatant of H. pylori culture was used to study the mechanism of apoptosis induction in human leukaemia T cell lines Jurkat and CEM and in primary T cells. The cytotoxin associated gene A (CagA) and vacuolating cytotoxin A (Vac A) positive bacterial strain H. pylori 60190 (CagA+, VacA+) and as a control the less toxic H. pylori strain Tx30a (CagA-, VacA-) were used to produce the supernatant. Cell death was determined by DNA fragmentation and protein expression by Western blot. Results H. pylori 60190-induced apoptosis was neither blocked by inhibition of the death ligands TRAIL (TNF-related apoptosis-inducing ligand), CD95L/FasL and TNF-alpha (tumour necrosis factor-a) in wild type Jurkat cells nor in FADD(def) (Fas-associated death domain protein) and caspase-8(def) subclones of the Jurkat cell line. Yet, the pancaspase inhibitor zVAD-fmk could inhibit up to 90% of H. pylori-induced apoptosis. Stable transfection of Jurkat wild type cells with Bcl-x(L and) Bcl-2 resulted in marked reduction of H. pylori-induced apoptosis, showing that the mitochondrial pathway is the key regulator. This is supported by the finding that surviving primary human lymphocytes upregulate Bcl-2 when exposed to H. pylori supernatant. Conclusions H. pylori-induced apoptosis of T cells is mediated by the mitochondrial pathway and could create a local environment that facilitates life-long infection by immune evasion
    Type of Publication: Journal article published
    PubMed ID: 17217377
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  • 5
    Keywords: RECEPTOR ; APOPTOSIS ; CELLS ; EXPRESSION ; CELL ; Germany ; human ; DEATH ; CLONING ; GENE-EXPRESSION ; PROTEIN ; SAMPLE ; SAMPLES ; DIFFERENTIATION ; LIGAND ; MECHANISM ; CONTRAST ; mechanisms ; IN-SITU ; NEOPLASIA ; CELL-DEATH ; DECREASE ; RECEPTORS ; SMALL-INTESTINE ; TRAIL ; protein expression ; LACKING ; molecular ; RECOMBINANT ; MOLECULAR-MECHANISM ; VARIANT ; INCREASE ; CELL-SURFACE EXPRESSION ; PH ; regulation ; development ; MOLECULAR-MECHANISMS ; methods ; cell death ; CELIAC-DISEASE ; death receptor ; USA ; LIGAND TRAIL ; HOMEOSTASIS ; INCREASES ; apoptotic ; MUCOSAL ; ACYL-COA-SYNTHETASE-5 ; HUMAN SMALL-INTESTINE ; IMPAIRED EXPRESSION
    Abstract: Background & Aims: The constant renewal of enterocytes along the crypt-villus axis (CVA) of human small intestine is due to cell-inherent changes resulting in the apoptotic cell death of senescent enterocytes. The aim of the present study was to examine underlying molecular mechanisms of the cell death at the villus tip. Methods: Characterization of human acyl-coenzyme A (CoA) synthetase 5 (ACSL5) was performed by cloning, recombinant protein expression, biochemical approaches, and several functional and in situ analyses. Results: Our data show that different amounts of acyl-CoA synthetase 5-full length (ACSL5-fl) and a so far unknown splice variant lacking exon 20 (ACSL5-Delta 20) are found in human enterocytes. In contrast with the splice variant ACSL5-Delta 20, recombinant and purified ACSL5-fl protein is active at a highly alkaline pH. Over expression of ACSL5-fl protein is associated with a decrease of the anti-apoptotic FLIP protein in a ceramide-dependent manner and an increased cell-surface expression of the death receptor TRAIL-RI. Expression analyses revealed that the ACSL5-fl/ACSL5-Delta 20 ratio increases along the CVA, thereby sensitizing ACSL5-fl-dominated cells at the villus tip to the death ligand TRAIL, which is corroborated by functional studies with human small intestinal mucosal samples and an immortalized human small intestinal cell fine. Conclusions: Our results suggest an ACSL5-dependent regulatory mechanism that contributes to the cellular renewal along the CVA in human small intestine. Deregulation of the ACSL5-fl/ACSL5-Delta 20 homeostasis in the maturation and shedding of cells along the CVA might also be of relevance for the development of intestinal neoplasia
    Type of Publication: Journal article published
    PubMed ID: 17681178
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  • 6
    Keywords: RECEPTOR ; APOPTOSIS ; CANCER ; CANCER CELLS ; CELLS ; IN-VITRO ; tumor ; TUMOR-CELLS ; CELL ; COMBINATION ; Germany ; human ; IN-VIVO ; TOXICITY ; VITRO ; DEATH ; RISK ; RNA ; cell line ; LINES ; ACTIVATION ; LIGAND ; MECHANISM ; colon ; hepatocytes ; CELL-LINES ; DOWN-REGULATION ; treatment ; UP-REGULATION ; CELL-LINE ; LINE ; CANCER-CELLS ; cell lines ; pancreatic cancer ; TUMOR CELLS ; TRAIL ; MULTIPLE-MYELOMA ; HUMAN HEPATOCYTES ; APOPTOSIS-INDUCING LIGAND ; RE ; PANCREATIC-CANCER ; CAPACITY ; INTERFERENCE ; RNA INTERFERENCE ; pancreatic ; TUMOR-CELL ; CHEMOTHERAPEUTIC DRUGS ; LIGAND TRAIL ; NECROSIS ; HEPATOCELLULAR-CARCINOMA CELLS ; comparison ; BORTEZOMIB ; CAUSAL ROLE ; PROTEASOME INHIBITION
    Abstract: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) represents a novel promising anticancer biotherapeutic. However, TRAIL-resistant tumor cells require combinatorial regimens to sensitize tumor but not normal cells for TRAIL-induced apoptosis. Here, we investigated the mechanism of the synergistic antitumor effect of bortezomib in combination with TRAIL in hepatoma, colon, and pancreatic cancer cells in comparison to the toxicity in primary human hepatocytes (PHH). TRAIL cotreatment at high but clinically relevant concentrations of bortezomib caused toxicity in PHH which potentially limits the clinical applicability of bortezomib/TRAIL cotreatment. However, at low concentrations of bortezomib TRAIL-resistant hepatoma, colon and pancreatic cancer cell lines but not PHH were efficiently sensitized for TRAIL-induced apoptosis. RNA interference and TRAIL receptor blockage experiments revealed that in bortezomib-treated hepatoma cells TRAIL-R1/TRAIL-R2 up-regulation, enhanced TRAIL DISC formation and cFLIP(L) down-regulation in addition to accumulation of Bak cooperatively sensitized for TRAIL. Bim, although accumulated upon bortezomib treatment, did not play a causal role for TRAIL sensitization in Hep3b cells. Combined treatment with bortezomib and TRAIL massively reduced the clonogenic capacity of hepatoma cells in vitro. Surviving clones could be resensitized for repeated TRAIL treatment. Conclusion: Bortezomib/TRAIL cotreatment bears the risk of severe hepatoroxicity at high but clinically relevant concentrations of bortezomib. However, within a wide therapeutic window bortezomib sensitized different cancer cells but not PHH for TRAIL-induced apoptosis
    Type of Publication: Journal article published
    PubMed ID: 17326159
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  • 7
    Keywords: brain ; APOPTOSIS ; CELLS ; EXPRESSION ; IN-VITRO ; tumor ; CELL ; Germany ; human ; IN-VIVO ; INHIBITION ; KINASE ; PATHWAY ; VITRO ; PROTEIN ; RNA ; TUMORS ; BIOLOGY ; MOLECULAR-BIOLOGY ; PHOSPHORYLATION ; resistance ; genetics ; CANCER-CELLS ; ONCOGENE ; GLUCOSE ; OVEREXPRESSION ; heredity ; MAP KINASES ; INTEGRIN ACTIVATION ; signaling ; molecular biology ; molecular ; ONCOLOGY ; RE ; BRAIN-TUMORS ; GLIOMA ; GLIOMA-CELLS ; TRANSPORTER ; brain tumors ; LEVEL ; analysis ; PHOSPHOPROTEIN ; ENGLAND ; GLIOBLASTOMA ; ASTROCYTES ; CYTOPLASMIC SEQUESTRATION ; DEATH EFFECTOR DOMAIN ; ERK1/2 ; PEA-15/PED ; PED/PEA-15
    Abstract: PEA-15 ( phosphoprotein enriched in astrocytes 15 kDa) is a death effector domain-containing protein, which is involved in the regulation of apoptotic cell death. Since PEA-15 is highly expressed in cells of glia l origin, we studied the role of PEA-15 in human malignant brain tumors. Immunohistochemical analysis of PEA-15 expression shows strong immunoreactivity in astrocytomas and glioblastomas. Phosphorylation of PEA-15 at Ser(116) is found in vivo in perinecrotic areas in glioblastomas and in vitro after glucose deprivation of glioblastoma cells. Overexpression of PEA-15 induces a marked resistance against glucose deprivation-induced apoptosis, whereas small interfering RNA (siRNA)-mediated downregulation of endogenous PEA-15 results in the sensitization to glucose withdrawal-mediated cell death. This antiapoptotic activity of PEA-15 under low glucose conditions depends on its phosphorylation at Ser116. Moreover, siRNA-mediated knockdown of PEA-15 abolishes the tumorigenicity of U87MG glioblastoma cells in vivo. PEA-15 regulates the level of phosphorylated extracellular-regulated kinase ( ERK) 1/ 2 in glioblastoma cells and the PEA-15-dependent protection from glucose deprivation-induced cell death requires ERK1/2 signaling. PEA-15 transcriptionally upregulates the Glucose Transporter 3, which is abrogated by the inhibition of ERK1/2 phosphorylation. Taken together, our findings suggest that Ser(116)-phosphorylated PEA-15 renders glioma cells resistant to glucose deprivation-mediated cell death as encountered in poor microenvironments, for example in perinecrotic areas of glioblastomas
    Type of Publication: Journal article published
    PubMed ID: 17700518
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  • 8
    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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  • 9
    Keywords: brain ; CANCER ; CELLS ; EXPRESSION ; INVASION ; tumor ; TUMOR-CELLS ; CELL ; Germany ; IN-VIVO ; KINASE ; MODEL ; PATHWAY ; THERAPY ; TISSUE ; NF-KAPPA-B ; LIGAND ; MECHANISM ; FAMILY ; ACTIVATED PROTEIN-KINASE ; BINDING ; CD95 ligand ; NUMBER ; COMPLEX DISC ; ONCOLOGY ; RE ; FAMILIES ; THERAPIES ; MATRIX METALLOPROTEINASES ; GLIOMA ; MEDIATED APOPTOSIS ; SRC FAMILY KINASES ; MOLECULAR-MECHANISMS ; TECHNOLOGY ; USA ; GLIOBLASTOMA ; matrix metalloproteinase ; FAS-INDUCED APOPTOSIS ; MATRIX-METALLOPROTEINASE ; HUMAN GLIOMA-CELLS ; TRIMERIZATION DOMAIN
    Abstract: Invasion of surrounding brain tissue by isolated tumor cells represents one of the main obstacles to a curative therapy of glioblastoma multiforme. Here we unravel a mechanism regulating glioma infiltration. Tumor interaction with the surrounding brain tissue induces CD95 Ligand expression. Binding of CD95 Ligand to CD95 on glioblastoma cells recruits the Src family member Yes and the p85 subunit of phosphatidylinositol 3-kinase to CD95, which signal invasion via the glycogen synthase kinase 3-beta pathway and subsequent expression of matrix metalloproteinases. In a murine syngeneic model of intracranial GBM, neutralization of CD95 activity dramatically reduced the number of invading cells. Our results uncover CD95 as an activator of P13K and, most importantly, as a crucial trigger of basal invasion of glioblastoma in vivo
    Type of Publication: Journal article published
    PubMed ID: 18328427
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  • 10
    Keywords: RECEPTOR ; proliferation ; ACTIVATION ; DENDRITIC CELLS ; TOLERANCE ; CYTOKINE ; REGULATORY T-CELLS ; SKIN-LESIONS ; TNF FAMILY-MEMBER ; TRANCE
    Abstract: Recently, it was discovered that the receptor activator of nuclear factor kappa B (RANK)/RANK ligand (RANKL) is part of an important signal transduction pathway for tissue homoeostasis. Therefore, we were interested in investigating RANKL expression in the epidermis of skin lesions from patients with different subtypes of cutaneous lupus erythematosus (CLE) and psoriasis as well as normal healthy donors. Using the tissue microarray technique, skin biopsy specimens were evaluated by immunohistochemistry. RANKL showed a significantly increased expression in the epidermis of skin biopsy specimens from patients with psoriasis (median: 4, range: 0-5) compared to patients with CLE (median: 0, range: 0-4) (P 〈 0.001). No significant differences in epidermal RANKL expression between the CLE subtypes were detected. These data show a different expression of RANKL in the epidermis of skin lesions from patients with CLE compared to those with psoriasis suggesting that RANKL might play an important role in the pathogenesis of the disease.
    Type of Publication: Journal article published
    PubMed ID: 21692859
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