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4 results on '"Annika Kessler"'

1. Specific Targeting of Antiapoptotic Bcl-2 Proteins as a Radiosensitizing Approach in Solid Tumors

Author

Benjamin Sobol, Osama Azzam Nieto, Emily Lara Eberlein, Anna-Lena Scherr, Lars Ismail, Annika Kessler, Luisa Nader, Maximilian Schwab, Paula Hoffmeister, Nathalie Schmitt, Dirk Jäger, Stefan Welte, Katharina Seidensaal, Petros Christopoulos, Christoph Heilig, Katharina Kriegsmann, Stefan Fröhling, Mark Kriegsmann, Jochen Hess, and Bruno Christian Köhler

Subjects
Bcl-2, Mc-1, Bcl-xL, radiotherapy, therapy resistance, cell death, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Avoidance of therapy-induced apoptosis is a hallmark of acquired resistance towards radiotherapy. Thus, breaking resistance still challenges modern cancer therapy. The Bcl-2 protein family is known for its regulatory role in apoptosis signaling, making Bcl-2, Mcl-1 and Bcl-xL promising targets. This study evaluates the effects of highly specific inhibitors for Bcl-xL (WEHI-539), Bcl-2 (ABT-199) and Mcl-1 (S63845) as radiosensitizers. Covering a broad spectrum of solid tumors, Non-Small-Cell Lung Cancer (NSCLC), Head and Neck Squamous Cell Carcinoma (HNSCC) and synovial sarcoma cell lines were exposed to fractionated radiation as standard therapy with or without Bcl-2 protein inhibition. Protein expression was detected by Western blot and cell death was assessed by flow cytometry measuring apoptosis. In contrast to NSCLC, a high level of Bcl-xL and its upregulation during radiotherapy indicated radioresistance in HNSCC and synovial sarcoma. Radioresistant cell lines across all entities benefited synergistically from combined therapy with Bcl-xL inhibition and fractionated radiation. In NSCLC cell lines, Mcl-1 inhibition significantly augmented radiotherapy independent of the expression level. Our data suggest that among antiapoptotic Bcl-2 proteins, targeting Bcl-xL may break resistance to radiation in HNSCC, synovial sarcoma and NSCLC in vitro. In NSCLC, Mcl-1 might be a promising target that needs further investigation.

Published
2022
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2. <scp> Bcl‐x L </scp> as prognostic marker and potential therapeutic target in cholangiocarcinoma

Author

Paula Hoffmeister‐Wittmann, Andreas Mock, Federico Nichetti, Felix Korell, Christoph E. Heilig, Anna‐Lena Scherr, Michael Günther, Thomas Albrecht, Eblina Kelmendi, Kaiyu Xu, Luisa Nader, Annika Kessler, Nathalie Schmitt, Sarah Fritzsche, Sofia Weiler, Benjamin Sobol, Albrecht Stenzinger, Stefan Boeck, Christoph B. Westphalen, Klaus Schulze‐Osthoff, Jörg Trojan, Thomas Kindler, Wilko Weichert, Karsten Spiekermann, Michael Bitzer, Gunnar Folprecht, Anna L. Illert, Melanie Boerries, Frederick Klauschen, Sebastian Ochsenreither, Jens Siveke, Sebastian Bauer, Hanno Glimm, Benedikt Brors, Jennifer Hüllein, Daniel Hübschmann, Sebastian Uhrig, Peter Horak, Simon Kreutzfeldt, Jesus M. Banales, Christoph Springfeld, Dirk Jäger, Peter Schirmacher, Stephanie Roessler, Steffen Ormanns, Benjamin Goeppert, Stefan Fröhling, and Bruno C. Köhler

Subjects
Cholangiocarcinoma, Hepatology, Medizin, Chemotherapy, Mcl-1, Apoptosis, Bcl-2, Bcl-x(L)
Abstract

Intrahepatic, perihilar, and distal cholangiocarcinoma (iCCA, pCCA, dCCA) are highly malignant tumours with increasing mortality rates due to therapy resistances. Among the mechanisms mediating resistance, overexpression of anti-apoptotic Bcl-2 proteins (Bcl-2, Bcl-x(L), Mcl-1) is particularly important. In this study, we investigated whether antiapoptotic protein patterns are prognostically relevant and potential therapeutic targets in CCA. Bcl-2 proteins were analysed in a pan-cancer cohort from the NCT/DKFZ/DKTK MASTER registry trial (n = 1140, CCA n = 72) via RNA-sequencing and transcriptome-based protein activity interference revealing high ranks of CCA for Bcl-x(L) and Mcl-1. Expression of Bcl-x(L), Mcl-1, and Bcl-2 was assessed in human CCA tissue and cell lines compared with cholangiocytes by immunohistochemistry, immunoblotting, and quantitative-RT-PCR. Immunohistochemistry confirmed the upregulation of Bcl-x(L) and Mcl-1 in iCCA tissues. Cell death of CCA cell lines upon treatemnt with specific small molecule inhibitors of Bcl-x(L) (Wehi-539), of Mcl-1 (S63845), and Bcl-2 (ABT-199), either alone, in combination with each other or together with chemotherapeutics was assessed by flow cytometry. Targeting Bcl-x(L) induced cell death and augmented the effect of chemotherapy in CCA cells. Combined inhibition of Bcl-x(L) and Mcl-1 led to a synergistic increase in cell death in CCA cell lines. Correlation between Bcl-2 protein expression and survival was analysed within three independent patient cohorts from cancer centers in Germany comprising 656 CCA cases indicating a prognostic value of Bcl-x(L) in CCA depending on the CCA subtype. Collectively, these observations identify Bcl-x(L) as a key protein in cell death resistance of CCA and may pave the way for clinical application.

Published
2022

3. Bcl-x

Author

Paula, Hoffmeister-Wittmann, Andreas, Mock, Federico, Nichetti, Felix, Korell, Christoph E, Heilig, Anna-Lena, Scherr, Michael, Günther, Thomas, Albrecht, Eblina, Kelmendi, Kaiyu, Xu, Luisa, Nader, Annika, Kessler, Nathalie, Schmitt, Sarah, Fritzsche, Sofia, Weiler, Benjamin, Sobol, Albrecht, Stenzinger, Stefan, Boeck, Christoph B, Westphalen, Klaus, Schulze-Osthoff, Jörg, Trojan, Thomas, Kindler, Wilko, Weichert, Karsten, Spiekermann, Michael, Bitzer, Gunnar, Folprecht, Anna L, Illert, Melanie, Boerries, Frederick, Klauschen, Sebastian, Ochsenreither, Jens, Siveke, Sebastian, Bauer, Hanno, Glimm, Benedikt, Brors, Jennifer, Hüllein, Daniel, Hübschmann, Sebastian, Uhrig, Peter, Horak, Simon, Kreutzfeldt, Jesus M, Banales, Christoph, Springfeld, Dirk, Jäger, Peter, Schirmacher, Stephanie, Roessler, Steffen, Ormanns, Benjamin, Goeppert, Stefan, Fröhling, and Bruno C, Köhler

Subjects
Cholangiocarcinoma, Bile Ducts, Intrahepatic, Proto-Oncogene Proteins c-bcl-2, Bile Duct Neoplasms, Cell Line, Tumor, bcl-X Protein, Humans, Myeloid Cell Leukemia Sequence 1 Protein, Prognosis
Abstract

Intrahepatic, perihilar, and distal cholangiocarcinoma (iCCA, pCCA, dCCA) are highly malignant tumours with increasing mortality rates due to therapy resistances. Among the mechanisms mediating resistance, overexpression of anti-apoptotic Bcl-2 proteins (Bcl-2, Bcl-x

Published
2022

4. RELB activation drives tumour aggressiveness and predicts prognosis in hepatocellular carcinoma

Author

Luisa Nader, Federico Nichetti, Anna-Lena Scherr, Christin Elssner, Dirk Ridder, Sarah Fritzsche, Sofia Weiler, Thomas Albrecht, Annika Kessler, Nathalie Schmitt, Felix Korell, Liangtao Ye, Toni Urbanik, Christoph Heilig, Mohammad Rahbari, Lydia Brandl, Christoph Springfeld, Thomas Longerich, Henning Schulze-Bergkamen, Dirk Jäger, Stefan Fröhling, Peter Schirmacher, Beate Straub, Achim Weber, Mathias Heikenwälder, Enrico de Toni, Benjamin Goeppert, Stephanie Roessler, Kai Breuhahn, and Bruno Köhler

Subjects
Hepatology
Published
2022

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