The smac mimetic BV6 improves NK cell-mediated killing of rhabdomyosarcoma cells by simultaneously targeting tumor and effector cells

Rhabdomyosarcoma (RMS), the most common cancer of connective tissues in pediatrics, is often resistant to conventional therapies. One underlying mechanism of this resistance is the overexpression of Inhibitor of Apoptosi
Rhabdomyosarcoma (RMS), the most common cancer of connective tissues in pediatrics, is often resistant to conventional therapies. One underlying mechanism of this resistance is the overexpression of Inhibitor of Apoptosis (IAP) proteins, leading to a dysfunctional cell death program within tumor cells. Smac mimetics (SM) are small molecules that can reactivate the cell death program by antagonizing IAP proteins and thereby compensating their overexpression. Here, we report that SM sensitize two RMS cell lines (RD and RH30) toward natural killer (NK) cell-mediated killing on the one hand, and increase the cytotoxic potential of NK cells on the other. The SM-induced sensitization of RH30 cells toward NK cell-mediated killing is significantly reduced through blocking tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on NK cells prior to coculture. In addition, the presence of zVAD.fmk, a pancaspase inhibitor, rescues tumor cells from the increase in killing, indicating an apoptosis-dependent cell death. On the NK cell side, the presence of SM in addition to IL-2 during the ex vivo expansion leads to an increase in their cytotoxic activity against RH30 cells. This effect is mainly TNFα-dependent and partially mediated by NK cell activation, which is associated with transcriptional upregulation of NF-κB target genes such as IκBα and RelB. Taken together, our findings implicate that SM represent a novel double-hit strategy, sensitizing tumor and activating NK cells with one single drug.
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Metadaten
Author:Kyra Fischer, Sara Tognarelli, Stefanie Rösler, Cathinka Boedicker, Ralf Schubert, Alexander Steinle, Thomas Klingebiel, Peter Bader, Simone Fulda, Evelyn Ullrich
URN:urn:nbn:de:hebis:30:3-431745
URL:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5339542
DOI:http://dx.doi.org/10.3389/fimmu.2017.00202
ISSN:1664-3224
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=28326081
Parent Title (English):Frontiers in immunology
Publisher:Frontiers Media
Place of publication:Lausanne
Contributor(s):Gianfranco Pittari
Document Type:Article
Language:English
Date of Publication (online):2017/04/06
Date of first Publication:2017/03/07
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2017/04/06
Tag:BV6; RD cells; RH30 cells; natural killer cells; rhabdomyosarcoma; second mitochondria-derived activator of caspases mimetic
Volume:8
Issue:Art. 202
Pagenumber:11
First Page:1
Last Page:11
Note:
Copyright © 2017 Fischer, Tognarelli, Roesler, Boedicker, Schubert, Steinle, Klingebiel, Bader, Fulda and Ullrich. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
HeBIS PPN:424952629
Institutes:Medizin
Dewey Decimal Classification:610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0

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