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  • 1
    Keywords: SYSTEM ; CANCER ; APOPTOSIS ; THERAPY ; INDUCTION ; treatment ; CANCER-THERAPY ; TRAIL ; function ; CANCER-TREATMENT ; cancer therapy
    Type of Publication: Book chapter
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  • 2
    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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  • 3
    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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  • 4
    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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  • 5
    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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  • 6
    Keywords: APOPTOSIS ; CANCER ; CELLS ; TUMOR-CELLS ; carcinoma ; CELL ; Germany ; human ; IN-VIVO ; HEPATOCELLULAR-CARCINOMA ; PROTEIN ; RNA ; DRUG ; cell line ; LINES ; MICE ; NF-KAPPA-B ; ACTIVATION ; COMPLEX ; LIGAND ; COMPLEXES ; MECHANISM ; FAMILY ; tumour ; mechanisms ; SUFFICIENT ; CELL-LINES ; MEMBER ; MEMBERS ; treatment ; 5-FLUOROURACIL ; ANTITUMOR-ACTIVITY ; hepatocellular carcinoma ; resistance ; CARCINOMA CELLS ; CELL-LINE ; LINE ; CARCINOMA-CELLS ; RECRUITMENT ; sensitivity ; side effects ; CYTOTOXIC LIGAND TRAIL ; TRAIL ; CASPASE 8 ; DISC ; SIGNALING COMPLEX ; TRAIL-INDUCED APOPTOSIS ; APOPTOSIS-INDUCING LIGAND ; FLICE-INHIBITORY PROTEIN ; INTRACELLULAR REGULATION ; POTENT ; HUMAN CANCER ; CASPASE-8 ; CD95-MEDIATED APOPTOSIS ; cFLIP siRNA death receptor ; death-inducing signalling complex DISC ; DECOY RECEPTORS ; drug sensitivity ; POTENTIAL MECHANISM ; TUMORICIDAL ACTIVITY
    Abstract: Tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) exhibits potent antitumour activity upon systemic administration in mice without showing the deleterious side effects observed with other apoptosis-inducing members of the TNF family such as TNF and CD95L. TRAIL may, thus, have great potential in the treatment of human cancer. However, about 60% of tumour cell lines are not sensitive to TRAIL. To evaluate the mechanisms of tumour resistance to TRAIL, we investigated hepatocellular carcinoma (HCC) cell lines that exhibit differential sensitivity to TRAIL. Pretreatment with chemotherapeutic drugs, for example, 5-fluorouracil (5-FU), rendered the TRAIL-resistant HCC cell lines sensitive to TRAIL-induced apoptosis. Analysis of the TRAIL death-inducing signalling complex (DISC) revealed upregulation of TRAIL-R2. Caspase-8 recruitment to and its activation at the DISC were substantially increased after 5-FU sensitisation, while FADD recruitment remained essentially unchanged. 5-FU pretreatment downregulated cellular FLICE-inhibitory protein (cFLIP) and specific cFLIP downregulation by small interfering RNA was sufficient to sensitise TRAIL-resistant HCC cell lines for TRAIL-induced apoptosis. Thus, a potential mechanism for TRAIL sensitisation by 5-FU is the increased effectiveness of caspase-8 recruitment to and activation at the DISC facilitated by the downregulation of cFLIP and the consequent shift in the ratio of caspase-8 to cFLIP at the DISC
    Type of Publication: Journal article published
    PubMed ID: 15105837
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  • 7
    Keywords: APOPTOSIS ; CANCER ; Germany ; UP-REGULATION ; ONCOLOGY ; RE ; USA ; cancer research
    Type of Publication: Journal article published
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  • 8
    Keywords: APOPTOSIS ; CANCER ; CELLS ; EXPRESSION ; CELL ; Germany ; human ; INHIBITION ; ACTIVATION ; primary ; INDUCED APOPTOSIS ; UP-REGULATION ; sensitization ; TRAIL ; ONCOLOGY ; RE ; GLIOMA ; GLIOMA-CELLS ; C-FLIP ; USA ; cancer research ; HEPATOCELLULAR-CARCINOMA CELLS
    Type of Publication: Journal article published
    PubMed ID: 17975170
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  • 9
    Keywords: APOPTOSIS ; CANCER ; CELLS ; EXPRESSION ; GROWTH ; IN-VITRO ; INHIBITOR ; SURVIVAL ; tumor ; carcinoma ; CELL ; COMBINATION ; Germany ; IN-VIVO ; MODEL ; MODELS ; THERAPY ; VITRO ; VIVO ; PROTEINS ; SAMPLE ; SAMPLES ; TIME ; NF-KAPPA-B ; ACTIVATION ; LIGAND ; INDEX ; TISSUES ; CONTRAST ; ANTITUMOR-ACTIVITY ; TARGET ; MOUSE ; resistance ; CARCINOMA CELLS ; CELL-DEATH ; MEMBRANE ; CARCINOMA-CELLS ; adenocarcinoma ; NORMAL TISSUE ; REVEALS ; CHILDREN ; pancreatic cancer ; pancreatic carcinoma ; TRAIL ; HUMAN PROSTATE-CANCER ; TRAIL-INDUCED APOPTOSIS ; APOPTOSIS-INDUCING LIGAND ; DRUG-INDUCED APOPTOSIS ; INHIBITORS ; PANCREATIC-CANCER ; THERAPIES ; DECOY RECEPTORS ; development ; X-LINKED INHIBITOR ; pancreatic adenocarcinoma ; USA ; ANTAGONISTS ; pancreatic tumor ; IRRADIATION-INDUCED APOPTOSIS ; XIAP ; therapeutic ; ALPHA-DEPENDENT APOPTOSIS
    Abstract: Evasion of apoptosis is a characteristic feature of pancreatic cancer, a prototypic cancer that is refractory to current treatment approaches. Hence, there is an urgent need to design rational strategies that counter apoptosis resistance. To explore X-linked inhibitor of apoptosis (XIAP) as a therapeutic target in pancreatic cancer, we analyzed the expression of XIAP in pancreatic tumor samples and evaluated the effect of small molecule XIAP inhibitors alone and in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) against pancreatic carcinoma in vitro and in vivo. Here, we report that XIAP is highly expressed in pancreatic adenocarcinoma samples compared with normal pancreatic ducts. Small molecule XIAP inhibitors synergize with TRAIL to induce apoptosis and to inhibit long-term clonogenic survival of pancreatic carcinoma cells. In contrast, they do not reverse the lack of toxicity of TRAIL on nonmalignant cells in vitro or normal tissues in vivo, pointing to a therapeutic index. Most importantly, XIAP inhibitors cooperate with TRAIL to trigger apoptosis and suppress pancreatic carcinoma growth in vivo in two preclinical models, i.e., the chorioallantoic membrane model and a mouse xenograft model. Parallel immunohistochemical analysis of tumor tissue under therapy reveals that the XIAP inhibitor acts in concert with TRAIL to cause caspase-3 activation and apoptosis. In conclusion, our findings provide, for the first time, evidence in vivo that XIAP inhibitors prime pancreatic carcinoma cells for TRAM-induced apoptosis and potentiate the antitumor activity of TRAIL against established pancreatic carcinoma. These findings build the rationale for further (pre)clinical development of XIAP inhibitors and TRAIL against pancreatic cancer. [Cancer Res 2009;69(6):2425-34]
    Type of Publication: Journal article published
    PubMed ID: 19258513
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  • 10
    Keywords: MICE ; COMPLEX ; SUPERFAMILY ; TNF ; KAPPA-B ACTIVATION ; RHEUMATOID-ARTHRITIS ; STRUCTURAL BASIS ; CHAINS ; CHRONIC PROLIFERATIVE DERMATITIS ; K11-LINKED POLYUBIQUITINATION ; MEDIATED REGULATION ; NEMO
    Abstract: Members of the tumour necrosis factor (TNF) receptor superfamily have important functions in immunity and inflammation. Recently linear ubiquitin chains assembled by a complex containing HOIL-1 and HOIP (also known as RBCK1 and RNF31, respectively) were implicated in TNF signalling, yet their relevance in vivo remained uncertain. Here we identify SHARPIN as a third component of the linear ubiquitin chain assembly complex, recruited to the CD40 and TNF receptor signalling complexes together with its other constituents, HOIL-1 and HOIP. Mass spectrometry of TNF signalling complexes revealed RIP1 (also known as RIPK1) and NEMO (also known as IKK gamma or IKBKG) to be linearly ubiquitinated. Mutation of the Sharpin gene (Sharpin(cpdm/cpdm)) causes chronic proliferative dermatitis (cpdm) characterized by inflammatory skin lesions and defective lymphoid organogenesis. Gene induction by TNF, CD40 ligand and interleukin-1 beta was attenuated in cpdm-derived cells which were rendered sensitive to TNF-induced death. Importantly, Tnf gene deficiency prevented skin lesions in cpdm mice. We conclude that by enabling linear ubiquitination in the TNF receptor signalling complex, SHARPIN interferes with TNF-induced cell death and, thereby, prevents inflammation. Our results provide evidence for the relevance of linear ubiquitination in vivo in preventing inflammation and regulating immune signalling
    Type of Publication: Journal article published
    PubMed ID: 21455173
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