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  • 1
    Keywords: CELLS ; HEPATOCELLULAR-CARCINOMA ; MECHANISM ; COPY-NUMBER ; IMPORTIN-ALPHA ; HUMAN HOMOLOG ; SUSCEPTIBILITY GENE ; protein expression ; TARGET GENES ; SEGREGATION GENE CSE1
    Abstract: Proteins of the karyopherin superfamily including importins and exportins represent an essential part of the nucleocytoplasmic transport machinery. However, the functional relevance and regulation of karyopherins in hepatocellular carcinoma (HCC) is poorly understood. Here we identified cellular apoptosis susceptibility (CAS, exportin-2) and its transport substrate importin-alpha1 (imp-alpha1) among significantly up-regulated transport factor genes in HCC. Disruption of the CAS/imp-alpha1 transport cycle by RNAi in HCC cell lines resulted in decreased tumor cell growth and increased apoptosis. The apoptotic phenotype upon CAS depletion could be recapitulated by direct knockdown of the X-linked inhibitor of apoptosis (XIAP) and partially reverted by XIAP overexpression. In addition, XIAP and CAS mRNA expression levels were correlated in HCC patient samples (r=0.463; P〈0.01), supporting the in vivo relevance of our findings. Furthermore, quantitative mass spectrometry analyses of murine HCC samples (p53-/- versus p53+/+) indicated higher protein expression of CAS and imp-alpha1 in p53-/- tumors. Consistent with a role of p53 in regulating the CAS/imp-alpha1 transport cycle, we observed that both transport factors were repressed upon p53 induction in a p21-dependent manner. CONCLUSION: The CAS/imp-alpha1 transport cycle is linked to XIAP and is required to maintain tumor cell survival in HCC. Moreover, CAS and imp-alpha1 are targets of p53-mediated repression, which represents a novel aspect of p53's ability to control tumor cell growth in hepatocarcinogenesis.
    Type of Publication: Journal article published
    PubMed ID: 24799195
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  • 2
  • 3
    Keywords: CANCER ; CELLS ; IRRADIATION ; carcinoma ; CELL ; Germany ; THERAPY ; DEATH ; EXPOSURE ; radiation ; DNA ; REDUCTION ; SUFFICIENT ; FLOW ; treatment ; PARTICLES ; CARCINOMA CELLS ; CELL-DEATH ; CERVIX ; DAMAGE ; FRANCE ; BEAM ; bioshuttle ; BORON ; boron neutron capture therapy (BNCT) ; boronophenylalanine (BPA) ; CAPTURE THERAPY ; CARCINOMA-CELLS ; CELLULAR UPTAKE ; DELIVERY ; DNA-DAMAGE ; drug delivery ; LET-effects ; nuclear transport
    Abstract: Boron neutron capture therapy (BNCT) is an experimental treatment modality which depends on a sufficient cellular uptake of Boron (B-10) followed by an exposure to a thermal neutron beam from a. nuclear reactor. High energetic particles (He-4 and Li-7) are. created during the neutron capture reaction and produce DNA damages, which lead to cell killing. Regarding BNCT, the short radiation range of He- and Li-particles is decisive for the distribution of B-10. Until now, BNCT has been lacking for therapeutically effective concentrations of B-10. Twenty-four hours after the combined use of our 'Bioshuttle'-p-borono-phenylalanine(10)-constructs ('Bioshuttle'-p-BPA(10)) and neutron-irradiation, an obvious reduction of the radiation-resistant HeLa-S cells could be observed. No cells were alive 72 h after the incubation with 'Bioshuttle'-p-BPA(10) followed by neutron irradiation. A post-mitotic cell death could be assumed based on flow cytometrical data. (C) 2003 Editions scientifiques et medicales Elsevier SAS. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 12832130
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  • 4
    Keywords: RECEPTOR ; CANCER ; CELLS ; EXPRESSION ; proliferation ; tumor ; TUMOR-CELLS ; carcinoma ; CELL ; Germany ; DISEASE ; NEW-YORK ; TISSUE ; PATIENT ; DNA ; RECEPTOR EXPRESSION ; INDEX ; primary ; ASSOCIATION ; chromosome ; BREAST ; breast cancer ; BREAST-CANCER ; antibodies ; antibody ; hormone ; AMPLIFICATION ; immunohistochemistry ; AGE ; PROSTATE-CANCER ; ABERRATIONS ; IN-SITU HYBRIDIZATION ; p53 ; REGION ; PROGNOSTIC-FACTORS ; tumor size ; REGIONS ; EVOLUTION ; BREAST-CARCINOMA ; CARCINOMAS ; INVOLVEMENT ; PROGNOSTIC FACTORS ; OVEREXPRESSION ; FLOW-CYTOMETRY ; S-PHASE ; PROGNOSTIC FACTOR ; SECTIONS ; MITOSIS ; GENETIC INSTABILITY ; protein expression ; DNA-PLOIDY ; POSSIBLE MECHANISM ; primary breast cancer,genetic instability,prognostic significance
    Abstract: Our purpose was to assess the presence of centrosomal aberrations as measured by immunohistochemistry in primary invasive breast cancer and their association with established and proposed prognostic factors. Tissue sections of 103 primary invasive breast cancers were examined using centrosome-specific antibodies to pericentrin and gamma-tubulin. At least 3 different tumor regions per case were examined to determine maximum centrosomal aberration levels, which represent the proportion of cells with abnormal centrosomes in the region with the highest percentage of cells with centrosomal aberrations. The chi(2) test was performed to evaluate the association of maximum centrosomal aberration levels with patient age; tumor size; nodal status; nuclear grade; hormone receptor and Her2/neu expression; proportion of Ki67-, p53- and Bcl-2-positive tumor cells; DNA index; S-phase fraction; and proliferation index. With pericentrin immunohistochemistry, maximum centrosomal aberration levels 〉35% were detectable in 92 of the 103 breast carcinomas (89%). We found a highly significant correlation of maximum centrosomal aberration levels above 3S% with axillary nodal tumor involvement (p 〈 0.0001) and the absence of hormone receptors (p 〈 0.0001). In addition, there was a borderline significant relationship with age 〈50 years (p = 0.00) and Her2/neu overexpression (p = 0.050). Among node-negative patients, maximum centrosomal aberration levels 〉35% were also associated with an increased DNA index (p = 0.006). In a subset of patients, additional staining of centrosomes with a monoclonal anti-gamma-tubulin antibody essentially confirmed these results. In primary invasive breast cancer, centrosomal aberrations are associated with those factors predicting a more aggressive course of disease. This might indicate a fundamental role of centrosomal dysfunction in disease evolution, possibly as a result of chromosome missegregation during mitosis. (C) 2003 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 14506732
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  • 5
    Keywords: PEPTIDE ; CANCER ; CELLS ; EXPRESSION ; GROWTH ; tumor ; TUMOR-CELLS ; carcinoma ; CELL ; Germany ; human ; THERAPY ; GENE ; GENE-EXPRESSION ; GENES ; transcription ; LINES ; INFECTION ; INTERVENTION ; FLOW ; cell cycle ; CELL-CYCLE ; CYCLE ; E7 ; ACID ; ACIDS ; NUCLEIC-ACIDS ; gene expression ; p53 ; HIGH-RISK ; DNA-DAMAGE ; drug delivery ; HPV ; E6 ; EPITHELIAL-CELLS ; Jun ; PHENOTYPE ; CARCINOMAS ; CARRIERS ; HUMAN-PAPILLOMAVIRUS TYPE-16 ; INFECTIONS ; human papilloma virus ; BEHAVIOR ; FLOW-CYTOMETRY ; TUMOR CELLS ; ANTAGONIST ; PNA ; anti-gene ; cell-cycle-drug-effects ; EARLY GENES ; flow cytometry ; HPV type ; HUMAN CANCER ; immortalization ; oncogene-protein-E6 ; oncogeneprotein-E7 ; P53 GENE ; papillomaviruses ; peptide nucleic acid ; PRB ; RNA INTERFERENCE ; THERAPIES
    Abstract: Approximately 100% of cervical carcinomas are causally linked to infections with high-risk human papillomaviruses (HPVs), whose oncogenicity has been assigned to the continued expression of two early viral genes, E6 and E7. Reversal of the transformed phenotype by inhibiting E6/E7 gene expression therefore provides a suitable goal for tumor therapy. We established an application controlling the E6/E7 expression of the HPV type 18, by using viral gene directed peptide nucleic acids (PNAs). One consequence was the complete change in growth to a stagnated behavior of the HPV 18 positive HeLa-S cells. With flow cytometry, we investigated changes in the cell cycle and expression of the pRB (retinoblastoma) and p53 genes acting as antagonists to E6 and E7. We realized that application of PNAs via intracellular cleavable conjugated peptide carriers mediates specific inhibitory effects and we showed that the combined E6/E7-directed PNA-application mediated a clear morphological change from suspension to adherend state and the cells stopped growth. These data could demonstrate a promising approach for development of new 'anti-gene therapeutics' against papillomavirus-induced human cancers. (C) 2004 Elsevier Ireland Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 15145519
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  • 6
    Keywords: CELLS ; GROWTH ; IRRADIATION ; carcinoma ; Germany ; MODEL ; SYSTEM ; EXPOSURE ; radiation ; TIME ; DNA ; INDUCTION ; RAT ; RATS ; FLOW ; cell cycle ; CYCLE ; treatment ; BREAST-CANCER ; PROGRESSION ; CARCINOMAS ; DOSE-RATE BRACHYTHERAPY ; INITIATION ; CYCLE ARREST ; cell cycle progression ; animal model ; DOSE-RATE ; low dose rate brachytherapy ; prostate Dunning tumour ; pulsed dose rate brachytherapy ; RATE INTERSTITIAL BRACHYTHERAPY
    Abstract: Purpose: The study consisted of two treatment arms comparing the effects of CLDR (continuous low dose rate) and PDR ( pulsed dose rate) brachytherapy on cell cycle progression in a radioresistant rat prostate tumour model. Materials and methods: Interstitial PDR and CLDR brachytherapy ( both 192-Ir, 0.75 Gy/h) were administered to Dunning prostate R3327-AT1 carcinomas transplanted subcutaneously into the thigh of Copenhagen rats. Increasing doses of up to 20 as well as up to 40 Gy were applied. Cell cycle distributions of the aneuploid tumour cell subpopulations were determined at 4 h ( 3 Gy), 24 h ( 18 Gy), 48 h ( 20 and 36 Gy), as well as during the subsequent redistribution period ( 20 and 40 Gy) at 72, 96, and 120 h. Tumours either implemented with an empty tubing system (n = 5) or under undisturbed growth (n = 5) served as controls. Three animals were irradiated per time point and exposure condition. At least two flow cytometrical analyses were carried out per animal. Results: The aneuploid cells possessed a constant DNA-Index of 1.9 +/- 0.06. In contrast to sham-treated controls, the aneuploid cell fraction with G2/M DNA content was significantly increased (p 〈 0.05) after initiation of both, CLDR and PDR brachytherapy. However, CLDR resulted in an earlier accumulation of tumour cells in G2/M (24 h: 28% CLDR vs. 19% PDR, p 〈 0.05) with a concomitant reduction of cells in G1, whereas PDR yielded delayed, but then more pronounced cell cycle changes, particularly expressed during the redistribution period after both 20 and 40 Gy. Conclusion: CLDR and PDR brachytherapy showed differential effects on cell cycle progression. The induction of a significantly earlier but also less persistent G2/M cell cycle arrest after CLDR compared to PDR brachytherapy implies that a substantially higher fraction of tumour cells are irradiated in G2/M after CLDR
    Type of Publication: Journal article published
    PubMed ID: 16638716
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  • 7
    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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  • 8
    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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  • 9
    Keywords: APOPTOSIS ; CANCER ; CELLS ; GROWTH ; INHIBITOR ; SURVIVAL ; tumor ; TUMOR-CELLS ; CELL ; Germany ; KINASE ; THERAPY ; GENE-EXPRESSION ; DIFFERENTIATION ; ACTIVATION ; primary ; prognosis ; CELL-CYCLE ; ANTITUMOR-ACTIVITY ; TARGET ; NERVOUS-SYSTEM ; BONE-MARROW-TRANSPLANTATION ; STRATEGIES ; CHILDREN ; REPRESSION ; RETINOIC ACID ; 13-CIS-RETINOIC ACID ; INHIBITORS ; ONCOLOGY ; RE ; TUMOR-SUPPRESSOR ; THERAPIES ; LEVEL ; SUPPRESSOR ; USA ; BREAST-CANCER CELLS ; cell cycle arrest ; E2F-1 regulated genes ; epigenetic therapy ; HC-TOXIN ; HUMAN NEURO-BLASTOMA ; RB tumor suppressor network
    Abstract: The survival rate of children with advanced neuroblastoma (NB) is dismal despite intensive multimodal therapy. The limited efficacy and the frequent and serious side effects of currently used therapeutic regimens necessitate the development of new, less toxic treatment strategies. This study shows that the histone deacetylase inhibitor Helminthosporium carbonum (HC)-toxin suppresses the malignant phenotype of both established NB cell lines and primary NB cells with and without amplified MYCN at dosages lower than 20 nM. HC-toxin induces cell cycle arrest and apoptosis as well as neuronal differentiation and diminishes both colony formation and invasive growth. These cellular changes are accompanied by the transcriptional repression of cell cycle regulators of the retinoblastoma (RB) tumor suppressor network found at high levels in NBs with poor prognosis, like E2F-1 and its targets Skp2, N-myc, Mad2 and survivin. The levels of the hypophosphorylated active form of RB, and of cyclin-dependent kinase inhibitors including P15(INK4b), p16(INK4a), p21(cip1/waf-1) and p27(kip1) are increased. In conclusion, nanomolar doses of the HDACI HC-toxin cause a shift to a differentiated and benign phenotype of NB cells that is associated with an activation of the RB tumor suppressor network. (c) 2007 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 18074352
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  • 10
    Keywords: CANCER ; CELLS ; GROWTH ; IN-VITRO ; INHIBITOR ; SURVIVAL ; tumor ; CELL ; Germany ; VITRO ; GENE-EXPRESSION ; PROTEIN ; PROTEINS ; DIFFERENTIATION ; ACTIVATION ; primary ; CELL-LINES ; ANTITUMOR-ACTIVITY ; culture ; ACID ; RATES ; CELL-LINE ; acetylation ; HIGH-RISK ; HISTONE DEACETYLASE ; Ras ; retinoids ; neuroblastoma ; N-MYC ; ONCOLOGY ; RE ; TUMOR-SUPPRESSOR ; LEVEL ; HISTONE DEACETYLASE INHIBITORS ; SUPPRESSOR ; SODIUM VALPROATE ; retinoblastoma ; tumor suppressor ; HC-TOXIN ; RB tumor suppressor network ; E2F-1 ; HIGH-RISK NEUROBLASTOMA ; SUPPRESSES
    Abstract: Treatment of high-risk neuroblastoma (NB) is difficult. Novel therapeutics improving survival rates are urgently required. We have previously shown that the histone deacetylase inhibitor (HDACI) Helminthosporium carbonum (HC)toxin induces differentiation of neuroblastoma (NB) cells. Here, we show that HC-toxin inhibits the growth of both established NB cell lines and primary cultures with and without amplified MYCN stronger than retinoids (RAs) and other HDACIs (MS-275, n-butyric acid, suberoylanilide hydroxamic acid, trichostatin A, valproic acid). Nanomolar dosages suppress E2F-1, N-myc, Skp2, Mad2 and survivin proteins, found at high levels in high-risk NBs, more efficiently than both RAs and other HDACIs. The level of hypophosphorylated active retinoblastoma (RB) tumor suppressor protein is increased most effectively. HC-toxin's epoxy group is essential for inhibiting HDACs and promoting anti-NB activity. Without this functional group, those cellular effects are not observed. In conclusion, the anti-NB activity of HC-toxin is superior to that of RAs and that of all other HDACIs tested. (C) 2008 Elsevier Ireland Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 18262346
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