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Lookup NU author(s): Professor Jaap van Laar, Dr Anja Krippner-Heidenreich
In the lymph node (LN) environment, chronic lymphocytic leukemia (CLL) cells display increased NF-kappa B activity compared with peripheral blood CLL cells, which contributes to chemoresistance. Antagonists of cellular inhibitor of apoptosis proteins (cIAPs) can induce apoptosis in various cancer cells in a tumor necrosis factor-alpha (TNF alpha)-dependent manner and are in preclinical development. Smac-mimetics promote degradation of cIAP1 and cIAP2, which results in TNFR-mediated apoptosis via formation of a ripoptosome complex, comprising RIPK1, Fas-associated protein with death domain, FLICE-like inhibitory protein and caspase-8. CD40 stimulation of CLL cells in vitro is used as a model to mimic the LN microenvironment and results in NF-kappa B activation and TNF alpha production. In this study, we investigated the response of CLL cells to smac-mimetics in the context of CD40 stimulation. We found that treatment with smac-mimetics results in cIAP1 and cIAP2 degradation, yet although TNF alpha is produced, this did not induce apoptosis. Despite the presence of all components, the ripoptosome complex did not form upon smac-mimetic treatment in CLL cells. Thus, CLL cells seem to possess aberrant upstream NF-kappa B regulation that prevents ripoptosome formation upon IAP degradation. Unraveling the exact molecular mechanisms of disturbed ripoptosome formation may offer novel targets for treatment in CLL.
Author(s): Maas C, Tromp JM, van Laar J, Thijssen R, Elias JA, Malara A, Krippner-Heidenreich A, Silke J, van Oers MHJ, Eldering E
Publication type: Article
Publication status: Published
Journal: Cell Death and Disease
Year: 2013
Volume: 4
Online publication date: 29/08/2013
Acceptance date: 17/07/2013
Date deposited: 19/01/2015
ISSN (electronic): 2041-4889
Publisher: Nature Publishing Group
URL: http://dx.doi.org/10.1038/cddis.2013.305
DOI: 10.1038/cddis.2013.305
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