TY  - JOUR
A1  - Rauert-Wunderlich, Hilka
A1  - Berberich, Ingolf
A1  - Rosenwald, Andreas
A1  - Rudelius, Martina
T1  - CD40L mediated alternative NF kappa B-signaling induces resistance to BCR-inhibitors in patients with mantle cell lymphoma
JF  - Cell Death & Disease
N2  - Drug resistance is a significant obstacle in cancer treatment and therefore a frequent subject of research. Developed or primary resistance limits the treatment success of inhibitors of the B cell receptor (BCR) pathway in mantle cell lymphoma (MCL) patients. Recent research has highlighted the role of the nuclear factor-kappa B (NF kappa B) pathway in the context of resistance to BCR inhibitors in MCL. In this study, we analyzed the dependency of MCL cell lines on NF kappa B signaling and illustrated the ability of CD40L to activate the alternative NF kappa B pathway in MCL. This activation leads to independency of classical NF kappa B signaling and results in resistance to BCR inhibitors. Therefore, ligands (such as CD40L) and their activation of the alternative NF kappa B pathway have a major impact on the drug response in MCL. Furthermore, this study indicates a protective role for cells expressing specific ligands as microenvironmental niches for MCL cells and underlines the significance of therapeutically targeting alternative NF kappa B signaling in MCL.
KW  - Bruton Tyrosine Kinase
KW  - Tumor Microenvironment
KW  - Targeted Therapies
KW  - Ibrutinib
KW  - Pathway
KW  - Malignancies
KW  - Activation
KW  - Ligand
KW  - Proliferation
KW  - PCI-32765
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-225027
IS  - 9
ER  - 
TY  - JOUR
A1  - Fischer, Roman
A1  - Maier, Olaf
A1  - Siegemund, Martin
A1  - Wajant, Harald
A1  - Scheurich, Peter
A1  - Pfizenmaier, Klaus
T1  - A TNF Receptor 2 Selective Agonist Rescues Human Neurons from Oxidative Stress-Induced Cell Death
JF  - PLoS ONE
N2  - Tumor necrosis factor (TNF) plays a dual role in neurodegenerative diseases. Whereas TNF receptor (TNFR) 1 is predominantly associated with neurodegeneration, TNFR2 is involved in tissue regeneration and neuroprotection. Accordingly, the availability of TNFR2-selective agonists could allow the development of new therapeutic treatments of neurodegenerative diseases. We constructed a soluble, human TNFR2 agonist (TNC-scTNF(R2)) by genetic fusion of the trimerization domain of tenascin C to a TNFR2-selective single-chain TNF molecule, which is comprised of three TNF domains connected by short peptide linkers. TNC-scTNFR2 specifically activated TNFR2 and possessed membrane-TNF mimetic activity, resulting in TNFR2 signaling complex formation and activation of downstream signaling pathways. Protection from neurodegeneration was assessed using the human dopaminergic neuronal cell line LUHMES. First we show that TNC-scTNF(R2) interfered with cell death pathways subsequent to H(2)O(2) exposure. Protection from cell death was dependent on TNFR2 activation of the PI3K-PKB/Akt pathway, evident from restoration of H(2)O(2) sensitivity in the presence of PI3K inhibitor LY294002. Second, in an in vitro model of Parkinson disease, TNC-scTNFR(2) rescues neurons after induction of cell death by 6-OHDA. Since TNFR2 is not only promoting anti-apoptotic responses but also plays an important role in tissue regeneration, activation of TNFR2 signaling by TNC-scTNF(R2) appears a promising strategy to ameliorate neurodegenerative processes.
KW  - Tumor-necrosis-factor
KW  - Glutamate-induced excitotoxicity
KW  - Single-chain TNF
KW  - Kappa-B pathway
KW  - Parkinsons-disease
KW  - Signaling complex
KW  - Activation
KW  - Apoptosis
KW  - Dopamine
KW  - Ligand
Y1  - 2011
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133552
VL  - 6
IS  - 11
ER  -