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Targeting cell death signaling in colorectal cancer:Current strategies and future perspectives

World Journal of Gastroenterology 2014年第8期20卷 1923-1934页

作者： Bruno Christian Koehler Dirk Jger henning schulze-bergkamen National Center for Tumor Diseases University Hospitals Heidelberg69120 HeidelbergGermany

The evasion from controlled cell death induction has been considered as one of the hallmarks of cancer cells. Defects in cell death signaling are a fundamental phenomenon in colorectal cancer. Nearly any non-invasive cancer treatment finally aims to induce cell death. However, apoptosis resistance is the major cause for insufficient therapeutic success and disease relapse in gastrointestinal oncology. Various compounds have been developed and evaluated with the aim to meet with this obstacle by triggering cell death in cancer cells. The aim of this review is to illustrate current approaches and future directions in targeting cell death signaling in colorectal cancer. The complex signaling network of apoptosis will be demonstrated and the “druggability” of targets will be identified. In detail, proteins regulating mitochondrial cell death in colorectal cancer, such as Bcl-2 and survivin, will be discussed with respect to potential therapeutic exploitation. Death receptor signaling and targeting in colorectal cancer will be outlined. Encouraging clinical trials including cell death based targeted therapies for colorectal cancer are under way and will be demonstrated. Our conceptual understanding of cell death in cancer is rapidly emerging and new types of controlled cellular death have been identified. To meet this progress in cell death research, the implication of autophagy and necroptosis for colorectal carcinogenesis and therapeutic approaches will also be depicted. The main focus of this topic highlight will be on the revelation of the complex cell death concepts in colorectal cancer and the bridging from basic research to clinical use.

关键词： Colorectal cancer Apoptosis Necroptosis Autophagy Clinical trial Bcl-2 proteins BH-3 mimetics Inflammatory bowel disease

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Genetics of hepatocellular carcinoma

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World Journal of Gastroenterology 2007年第16期13卷 2271-2282页

作者： Andreas Teufel Frank Staib Stephan Kanzler Arndt Weinmann henning schulze-bergkamen Peter R Galle Department of Medicine Johannes Gutenberg University Mainz Germany

The completely assembled human genome has made it possible for modern medicine to step into an era rich in genetic information and high-throughput genomic analysis. These novel and readily available genetic resources and analytical tools may be the key to unravel the molecular basis of hepatocellular carcinoma (HCC). Moreover, since an efficient treatment for this disease is lacking, further understanding of the genetic background of HCC will be crucial in order to develop new therapies aimed at selected targets. We report on the current status and recent developments in HCC genetics. Special emphasis is given to the genetics and regulation of major signalling pathways involved in HCC such as p53, Wnt- signalling, TGFβ, Ras, and Rb pathways. Furthermore, we describe the influence of chromosomal aberrations as well as of DNA methylation. Finally, we report on the rapidly developing field of genomic expression profiling in HCC, mainly by microarray analysis.

关键词： Hepatocellular carcinoma Liver cancer Genetics Genomics Chromosome Mutation Pathway

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TRAIL-induced apoptosis of hepatocellular carcinoma cells is augmented by targeted therapies

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World Journal of Gastroenterology 2009年第47期15卷 5924-5935页

作者： Bruno Christian Koehler Toni Urbanik Binje Vick Regina Johanna Boger Steffen Heeger Peter R Galle Marcus Schuchmann henning schulze-bergkamen First Department of Medicine Johannes Gutenberg-University Mainz55101 MainzGermany Steffen HeegerMerck KGaAMS-D Global Clinical Development Unit-Oncology64293 DarmstadtGermany National Center of Tumor Diseases Department of Medical OncologyUniversity Clinic of Heidelberg69120 HeidelbergGermany

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 *** cellswere treated with kinase inhibitors and chemotherapeutic *** 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 *** 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 ***,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 ***, 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 ***: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

关键词： Hepatocellular carcinoma Apoptosis Tumor necrosis factor-related apoptosis inducing ligand BCL-xL MCL-1 5-fluorouracil Doxorubicin Sorafenib Phosphoinositol-3-kinase (Mitogen-activated protein kinase)/(extracellular signal regulated kinase) kinase c-Jun N-terminal kinase

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CYLD deletion triggers nuclear factor-κB-signaling and increases cell death resistance in murine hepatocytes

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World Journal of Gastroenterology 2014年第45期20卷 17049-17064页

作者： 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 National Center for Tumor Diseases Department of Medical Oncology University Clinic of Heidelberg 69120 HeidellbergBade-WuerrtembergGermany Institute of Pathology University Hospital Heidelberg 69120 HeidelbergBaden-WuerrtembergGermany Institute for Molecular Medicine Johannes Gutenberg-University Mainz 55131 MainzRheinland-PalatlnateGemany

AIM:To analyze the role of CYLD for receptor-mediated cell death of murine hepatocytes in acute liver injury ***: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 *** injury was assessed by measurement of serum transaminases and histological *** induction was quantified by cleaved PARP staining and Western blotting of activated *** factor(NF)-κB,ERK,Akt and jun amino-terminal kinases signaling were *** Hepatocytes were isolated by two step-collagenase perfusion and treated with recombinant TNF-αand with the CD95-ligand *** viability was analyzed by ***:Livers of CYLD-/-mice showed increased anti-apoptotic NF-κB *** both applied liver injury models CYLD-/-mice showed a significantly reduced apoptosis *** 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 *** 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,*** 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 ***:CYLD is a central regulator of apoptotic cell death in murine hepatocytes by controlling NF-κB dependent anti-apoptotic signaling.

关键词： CYLD Apoptosis Nuclear factor-κB Tumo rnecrosis factor-α CD95 Liver

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Bcl-x_L and Myeloid cell leukaemia-1 contribute to apoptosis resistance of colorectal cancer cells

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World Journal of Gastroenterology 2008年第24期14卷 3829-3840页

作者： 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 First Department of Medicine Johannes-Gutenberg-University Mainz German Cancer Research Center Institute of Pathology University of Mainz Department of Pathology Institute of Surgical PathologyUniversity Hospital Merck Pharma GmbH

AIM： TO explore the role of Bcl-XL and Myeloid cell leukaemia （Mcl）-I for the apoptosis resistance of colorectal carcinoma （CRC） cells towards current treatment modalities. METHODS： Bcl-XL and Mcl-1 mRNA and protein expression 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 plasmids, respectively. After modulation of protein expression, CRC cells were treated with chemotherapeutic agents, an antagonistic epidermal growth factor receptor （EGFR1） antibody, an EGFR1 tyrosine kinase inhibitor, or with the death receptor ligand TRAIL. Apoptosis induction and cell viability were analyzed. RESULTS： Here we show that in human CRC tissue 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 malignant 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 oxaliplatinand 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 transfection of an expression plasmid decreased chemotherapeutic drug-induced apoptosis. EGF treatment clearly induced Bcl-xL and Mcl-1 expression in CRC cells. Apoptosis 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

关键词： Colorectal carcinoma Bcl-XL Myeloid cellleukaemia-1 Epidermal growth factor receptor 1 Apoptosis 5-fluorouracil Irinotecan Oxaliplatin

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Outcome Results of Treatment with Selective Internal Radiation Therapy (SIRT) in Patients with Hepatocellular Carcinoma: A Single Center Experience

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Journal of Cancer Therapy 2017年第4期8卷 349-359页

作者： Jan Pfeiffenberger Tatjana Zimmermann Daniel N. Gotthardt Christoph Springfeld Wolfgang Stremmel Peter Schirmacher henning schulze-bergkamen Arianeb Mehrabi Christoph W. Michalski Katrin Hoffmann Nikolas Kortes Boris Radeleff Uwe Haberkorn Clemens Kratochwil Karl Heinz Weiss Carsten Grüllich Department of Gastroenterology and Hepatology University Hospital Heidelberg Heidelberg Germany Department of Medical Oncology National Center for Tumor Diseases Heidelberg University Hospital Heidelberg Heidelberg Germany Institute of Pathology University Hospital Heidelberg Heidelberg Germany Department of Gastroenterology and Oncology Marien-Hospital Wesel Germany Department of General and Transplant Surgery University Hospital Heidelberg Heidelberg Germany Department of Diagnostic and Interventional Radiology University Hospital Heidelberg Heidelberg Germany Department of Nuclear Medicine University Hospital Heidelberg Heidelberg Germany Liver Cancer Center Heidelberg University Hospital Heidelberg Heidelberg Germany

Background: Hepatocellular carcinoma (HCC) has a poor prognosis. Selective internal radiation therapy (SIRT) with microspheres is a treatment option for HCC. This study aimed to assess safety and survival (OS) in patients with HCC treated with SIRT, to stratify patients with tumor vascularization and analyze the impact of sequential sorafenib treatment. Methods: Thirty-nine patients who received SIRT for HCC between 2010 and 2013 at our center were included in this retrospective analysis. Tumor vascularization was assessed using a combination of MRI, MAA-scintigraphy and angiography. Tumor vascularization was correlated with survival. Subgroups are treated with two commercially available 90Y-labeled products SIR-Spheres (n = 16) and TheraSpheres (n = 23) and sequential therapy with sorafenib compared to SIRT only was analyzed. Results: Adverse events occurred in 49% of patients with only four grade 3 and no grade 4 event. Median survival for all patients was 12.5 months (95% CI: 8.7 - 16.3). No significant differences were detectable between Thera Spheres or SIR Spheres. Survival was shorter in patients with low tumor vascularization score (OS: 3.8 months (95% CI 0 - 15.0), p = 0.043). Survival was longer with sorafenib upon progression after SIRT (n=16) with an OS of 17.4 months (95% CI: 12.1 – 22.7) compared to no sorafenib (n = 13;9.1 months;95% CI: 3.0 - 15.1) or progression upon sorafenib before SIRT (n = 10;8.6 months;95% CI: 5.5 - 11.7). Conclusions: SIRT is safe in HCC patients. Tumor vascularization by radiography and scintigraphy may predict survival benefit. Sorafenib is active after SIRT and significantly prolongs survival.

关键词： SIRT Sorafenib Liver Cancer Y90

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Hordedane diterpenoid phytoalexins restrict Fusarium graminearum infection but enhance Bipolaris sorokiniana colonization of barley roots

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Molecular Plant 2024年第8期17卷 1307-1327页

作者： Yaming Liu Dario Esposto Lisa K.Mahdi Andrea Porzel Pauline Stark Hidayat Hussain Anja Scherr-henning Simon Isfort Ulschan.Bathe Ivan F.Acosta Alga Zuccaro Gerd U.Balcke Alain Tissier Department of Cell and Metabolic Biology Leibniz Institute of Plant BiochemistryHalleGermany Institute for Plant Sciences Cluster of Excellence on Plant Sciences(CEPLAS)Cologne BiocenterUniversity of CologneCologneGermany Department of Bioorganic Chemistry Leibniz Institute of Plant BiochemistryHalleGermany Max Planck Institute for Plant Breeding Research CologneGermany Horticultural Sciences University of FloridaGainesvilleFLUSA.

Plant immunity is a multilayered process that includes recognition of patterns or effectors from pathogens to elicit defense *** include the induction of a cocktail of defense metabolites that typically restrict pathogen ***,we investigate the interaction between barley roots and the fungal pathogens Bipolaris sorokiniana(Bs)and Fusarium graminearum(Fg)at the metabolite *** identify hordedanes,a previously undescribed set of labdane-related diterpenoids with antimicrobial properties,as critical players in these *** of barley roots by Bs and Fg elicits hordedane synthesis from a 60o-kb gene *** reconstruction of the biosynthesis pathway in yeast and Nicotiana benthamiana produced several hordedanes,including one of the most functionally decorated products 19-β-hydroxy-hordetrienoic acid(19-OH-HTA).Barley mutants in the diterpene synthase genes of this cluster are unable to produce hordedanes but,unexpectedly,show reduced Bs *** contrast,colonization by Fusarium graminearum,another fungal pathogen of barley and wheat,is 4-fold higher in the mutants completely lacking ***,19-OH-HTA enhances both germination and growth of Bs,whereas it inhibits other pathogenic fungi,including *** of microscopy and transcriptomics data suggest that hordedanes delay the necrotrophic phase of *** together,these results show that adapted pathogens such as Bs can subvert plant metabolic defenses to facilitate root colonization.

关键词： barley Hordeum vulgare diterpenoid phytoalexins gene cluster pathogenic fungi Bipolaris sorokininiana Fusarium graminearum

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ITPK1 is an InsP_(6)/ADP phosphotransferase that controls phosphate signaling in Arabidopsis

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Molecular Plant 2024年第7期17卷 1151-1157页

作者： Esther Riemer Danye Qiu Debabrata Laha Robert K.Harmel Philipp Gaugler Verena Gaugler Michael Frei Mohammad-Reza Hajirezaei Nargis Parvin Laha Lukas Krusenbaum Robin Schneider Adolfo Saiardi Dorothea Fiedler henning J.Jessen Gabriel Schaaf Ricardo F.H.Giehi 不详

(Molecular Plant 14,1864-1880;November 12021)We identified a mistake made when calculating the absolute concentrations of inositol(pyro)phosphates derived from CE-ESl-MS measurements reported in the originally published version of our *** to a calculation error when determining concentrations per fresh biomass,the absolute values shown in the manuscript are approximately 30-fold lower than they should *** mistake affects Figures 2D,3C,4C,and 7D and Figures S4,S11B,S13,and *** all conclusions made in the article referred to relative differences between genotypes and treatments,they remained unaffected by these mistakes.

关键词： ipt Arabidopsis absolute

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MYB34, MYB51, and MYB 122 Distinctly Regulate Indolic Glucosinolate Biosynthesis in Arabidopsis thaliana

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Molecular Plant 2014年第5期7卷 814-828页

作者： henning Frerigmann Tamara Gigolashvili Botanical Institute and Cluster of Excellence on Plant Sciences (CEPLAS) University of Cologne Cologne Biocenter D-50674 Cologne Germany

The MYB34, MYB51, and MYB122 transcription factors are known to regulate indolic glucosinolate （IG） biosynthesis in Arabidopsis thaliana. To determine the distinct regulatory potential of MYB34, MYB51, and MYB122, the accumulation of IGs in different parts of plants and upon treatment with plant hormones were analyzed in A. thaliana seedlings. It was shown that MYB34, MYB51, and MYB122 act together to control the biosynthesis of 13M in shoots and roots, with MYB34 controlling biosynthesis of IGs mainly in the roots, MYB51 regulating biosynthesis in shoots, and MYB122 having an accessory role in the biosynthesis of IGs. Analysis of glucosinolate levels in seedlings of myb34, myb51, myb122, myb34 myb51 double, and myb34 myb51 myb122 triple knockout mutants grown in the presence of abscisic acid （ABA）, salicylic acid （SA）, jasmonate （JA）, or ethylene （ET） revealed that：（1） MYB51 is the central regulator of IG synthesis upon SA and ET signaling, （2） MYB34 is the key regulator upon ABA and JA signaling, and （3） MYB122 plays only a minor role in JA/ET-induced glucosinolate biosynthesis. The myb34 myb51 myb122 triple mutant is devoid of IGs, indicating that these three MYB factors are indispensable for IG production under standard growth conditions.

关键词： indolic glucosinolates regulation R2R3 MYB the triple myb34 myb51 myb122 mutant.

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Organotypic hippocampal slices,an emerging tool to model synucleinopathies

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Neural Regeneration Research 2021年第5期16卷 999-1000页

作者： Sara Elfarrash Poul henning Jensen Department of Physiology Faculty of MedicineMansoura UniversityMansouraEgypt DANDRITE‑Danish Research Institute of Translational Neuroscience and Department of Biomedicine Aarhus UniversityAarhusDenmark

Parkinson’s disease(PD)is the second most common neurodegenerative disease after Alzheimer’s *** has been traditionally considered a motoric disorder characterized by tremor,rigidity and bradykinesia,however it is now settled that PD also comprises a range of non-motor symptoms like hyposmia,sleep disturbances and cognitive impairments(Tysnes and Storstein,2017).

关键词： Alzheimer impairment settled

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