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| 1 | TRAIL-induced apoptosis of hepatocellular carcinoma cells is augmented by targeted therapies显示文摘AIM:To analyze the effect of chemotherapeutic drugs and specific kinase inhibitors,in combination with the death receptor ligand tumor necrosis factor-related apoptosis inducing ligand(TRAIL),on overcoming TRAIL resistance in hepatocellular carcinoma(HCC)and to study the efficacy of agonistic TRAIL antibodies,as well as the commitment of antiapoptotic BCL-2 proteins, in TRAIL-induced apoptosis. METHODS:Surface expression of TRAIL receptors (TRAIL-R1-4)and expression levels of the antiapoptotic BCL-2 proteins MCL-1 and BCL-xL were analyzed by flow cytometry and Western blotting,respectively. Knock-down of MCL-1 and BCL-xL was performed by transfecting specific small interfering RNAs.HCC cellswere treated with kinase inhibitors and chemotherapeutic drugs.Apoptosis induction and cell viability were analyzed via flow cytometry and 3-(4,5-Dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. RESULTS:TRAIL-R1 and-R2 were profoundly expressed on the HCC cell lines Huh7 and Hep-G2. However,treatment of Huh7 and Hep-G2 with TRAIL and agonistic antibodies only induced minor apoptosis rates.Apoptosis resistance towards TRAIL could be considerably reduced by adding the chemotherapeutic drugs 5-fluorouracil and doxorubicin as well as the kinase inhibitors LY294002[inhibition of phosphoinositol- 3-kinase(PI3K)],AG1478(epidermal growth factor receptor kinase),PD98059(MEK1),rapamycin(mam- malian target of rapamycin)and the multi-kinase inhibitor Sorafenib.Furthermore,the antiapoptotic BCL-2 proteins MCL-1 and BCL-xL play a major role in TRAIL resistance:knock-down by RNA interference increased TRAIL-induced apoptosis of HCC cells.Additionally, knock-down of MCL-1 and BCL-xL led to a significant sensitization of HCC cells towards inhibition of both c-Jun N-terminal kinase and PI3K.CONCLUSION:Our data identify the blockage of survival kinases,combination with chemotherapeutic drugs and targeting of antiapoptotic BCL-2 proteins as promising ways to overcome TRAIL resistance in HCC. | Bruno Christian Koehler Toni Urbanik Binje Vick Regina Johanna Boger Steffen Heeger Peter R Galle Marcus Schuchmann Henning Schulze-Bergkamen | 2009 | World Journal of Gastroenterology2009，15，47： | 9 |
| 2 | Bcl-x_L and Myeloid cell leukaemia-1 contribute to apoptosis resistance of colorectal cancer cells显示文摘AIM: To explore the role of Bcl-xL and Myeloid cell leukaemia (Mcl)-1 for the apoptosis resistance of colorectal carcinoma (CRC) cells towards current treat-ment modalities. METHODS: Bcl-xL and Mcl-1 mRNA and protein ex-pression were analyzed in CRC cell lines as well as human CRC tissue by Western blot,quantitative PCRand immunohistochemistry. Bcl-xL and Mcl-1 protein expression was knocked down or increased in CRC cell lines by applying specific siRNAs or expression plas-mids,respectively. After modulation of protein expres-sion,CRC cells were treated with chemotherapeutic agents,an antagonistic epidermal growth factor recep-tor (EGFR1) antibody,an EGFR1 tyrosine kinase inhibi-tor,or with the death receptor ligand TRAIL. Apoptosis induction and cell viability were analyzed. RESULTS: Here we show that in human CRC tis-sue and various CRC cell lines both Bcl-xL and Mcl-1 are expressed. Bcl-xL expression was higher in CRC tissue than in surrounding non-malignant tissue,both on protein and mRNA level. Mcl-1 mRNA expression was significantly lower in ma-lignant tissues. However,protein expression was slightly higher. Viability rates of CRC cells were significantly decreased after knock down of Bcl-xL expression,and,to a lower extent,after knock down of Mcl-1 expression. Furthermore,cells with reduced Bcl-xL or Mcl-1 expression was more sensitive towards oxaliplatin-and irinotecan-induced apoptosis,and in the case of Bcl-xL also towards 5-FU-induced apoptosis. On the other hand,upregulation of Bcl-xL by transfec-tion of an expression plasmid decreased chemothera-peutic drug-induced apoptosis. EGF treatment clearly induced Bcl-xL and Mcl-1 expression in CRC cells. Apop-tosis induction upon EGFR1 blockage by cetuximab or PD168393 was increased by inhibiting Mcl-1 and Bcl-xL expression. More strikingly,CD95-and TRAIL-induced apoptosis was increased by Bcl-xL knock down. CONCLUSION: Our data suggest that Bcl-xL and,to a lower extent,Mcl-1,are important anti-apoptotic factors in CRC. Specific downregulation of Bcl-xL is a promising approach to sensitize CRC cells towards chemotherapy and targeted therapy. | Henning Schulze-Bergkamen Roland Ehrenberg Lothar Hickmann Binje Vick Toni Urbanik Christoph C Schimanski Martin R Berger Arno Schad Achim Weber Steffen Heeger Peter R Galle Markus Moehler | 2008 | World Journal of Gastroenterology2008，14，24： | 4 |
| 3 | CYLD deletion triggers nuclear factor-κB-signaling and increases cell death resistance in murine hepatocytes显示文摘AIM:To analyze the role of CYLD for receptor-mediated cell death of murine hepatocytes in acute liver injury models.METHODS:Hepatocyte cell death in CYLD knockout mice(CYLD-/-)was analyzed by application of liver injury models for CD95-(Jo2)and tumor necrosis factor(TNF)-α-[D-Gal N/lipopolysaccharide(LPS)]induced apoptosis.Liver injury was assessed by measurement of serum transaminases and histological analysis.Apoptosis induction was quantified by cleaved PARP staining and Western blotting of activated caspases.Nuclear factor(NF)-κB,ERK,Akt and jun amino-terminal kinases signaling were assessed.Primary Hepatocytes were isolated by two step-collagenase perfusion and treated with recombinant TNF-αand with the CD95-ligand Jo2.Cell viability was analyzed by MTT-assay.RESULTS:Livers of CYLD-/-mice showed increased anti-apoptotic NF-κB signaling.In both applied liver injury models CYLD-/-mice showed a significantly reduced apoptosis sensitivity.After D-Gal N/LPS treatment CYLD-/-mice exhibited significantly lower levels of alanine aminotransferase(ALT)(295 U/L vs 859 U/L,P<0.05)and aspartate aminotransferase(AST)(560 U/L vs 1025 U/L,P<0.01).After Jo injection CYLD-/-mice showed 2-fold lower ALT(50 U/L vs 110 U/L,P<0.01)and lower AST(250 U/L vs 435 U/L,P<0.01)serumlevels compared to WT mice.In addition,isolated CYLD-/-primary murine hepatocytes(PMH)were less sensitive towards death receptor-mediated apoptosis and showed increased levels of Bcl-2,XIAP,c IAP1/2,survivin and c-FLIP expression upon TNF-and CD95-receptor triggering,respectively.Inhibition of NF-κB activation by the inhibitor of NF-κB phosphorylation inhibitor BAY 11-7085 inhibited the expression of antiapoptotic proteins and re-sensitized CYLD-/-PMH towards TNF-and CD95-receptor mediated cell death.CONCLUSION:CYLD is a central regulator of apoptotic cell death in murine hepatocytes by controlling NF-κB dependent anti-apoptotic signaling. | Toni Urbanik Bruno Christian Koehler Laura Wolpert Christin Elbner Anna-Lena Scherr Thomas Longerich Nicole Kautz Stefan Welte Nadine Hovelmeyer Dirk Jager Ari Waisman Henning Schulze-Bergkamen | 2014 | World Journal of Gastroenterology2014，20，45： | 3 |
| 4 | Machine Direction Strength Theory of Corrugated Fiberboard显示文摘 | URBANIK T J | 1996 | Journal of Composites Technology &Research1996，18，2： | 1 |
| 5 | Application 3D DSA and angiographic CT in interventional neuroradiology显示文摘 | Brzegowy P Urbanik A Popiela TJ | | 0，，： | 1 |
| 6 | System partition technique toimprove signal coordination and traffic progression显示文摘 | TIAN Zong URBANIK T | 2007 | Journal of Transportation Engineering2007，133，2： | 1 |
| 7 | Short-term freeway traffic volume forecasting using radial basis function neural network显示文摘 | Byungkyu Park Messer C J Thomas Urbanik II | 1998 | Transporta- tion Research Record1998，，1651： | 1 |
| 8 | Application 3D DSA and angiographic CT in interventional neuroradiology显示文摘 | Brzegowy P Urbanik A Popiela TJ | 2010 | Przegl Lek2010，67，4： | 1 |
| 9 | Appli-cation 3D DSA and angiographic CT ininterventional neuroradiology显示文摘 | Brzegowy P Urbanik A Popiela TJ | 2010 | Przegl Lek2010，67，4： | 1 |
| 10 | System partition technique toimprove signal coordination and traffic progression显示文摘 | Tian Z Urbanik T | 2009 | Journal of Transportation Engineering2009，133，2： | 1 |
| 11 | Cranioplasty prosthesis manufacturing based on reverse engineering technology 显示文摘 | Chrzan R Urbanik A Karbowski K | 2012 | Med Sci Monit2012，18，1： | 1 |
| 12 | System partition technique to improve signal coordination and traffic progression显示文摘 | Tian Z Urbanik T | 2007 | Journal of Transportation Engineering2007，133，2： | 1 |
| 13 | Diagnostic imaging of sacroiliac joints and the spine in the course of spondyloarthmpathies 显示文摘 | Sudol-Szopinska I Urbanik A | 2013 | Pol J Radiol2013，78，2： | 1 |
| 14 | Polish medical society of radiology and polish society of rheumatology recommendations for magnetic resonance imaging of musculoskeletal disorders in rheumatology显示文摘 | Sudol-Szopinska I Urbanik A Wojciechowski W | 2015 | Pol J Radioi2015，80，1： | 1 |
| 15 | Cranioplasty prosthesis manufacturing based on reverse engineering technology显示文摘 | Chrzan R Urbanik A Karbowski K | 2012 | Medical Science Monitor: International Medical Journal of Experimental and Clinical Research2012，18，1： | 1 |
| 16 | Application 30 USA and angiographic CT in interxentional neuroradiology显示文摘 | Brzegowy P Urbanik A Popiela TJ | | 0，，04： | 1 |
| 17 | The Correlation Between Ion Beam/Material Interactions and Practical FIB Specimen Preparation显示文摘 | Prenitzer B I Urbanik Shannon C A Giannuzzi L A | 2003 | Microscopy and Micro- analysis2003，9，3： | 1 |
| 18 | State of the art in evacuation time estimates for nuclear power plants显示文摘 | Urbanik T | 1994 | International Journal of Mass Emergencies and Disasters1994，12，： | 1 |
| 19 | Impacts of intercycle demand fluctuations on delay 显示文摘 | Han Lee D Li Jan-Mou Urbanik Tom | 2009 | Journal of Transportation Engineering (S0733-947X)2009，135，5： | 1 |
| 20 | Evacuation time estimates for nuclear power plants显示文摘 | Urbanik T | 2000 | Journal of Hazardous Materials2000，75，23： | 1 |
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