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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 c.ristia. 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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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 c.ristia. 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 c.ristia. 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,Pction cYLD-/-mice showed 2-fold lower ALT(50 U/L vs 110 U/L,Pcompared 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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