CLL cells are resistant to smac mimetics because of an inability to form a ripoptosome complex

C Maas; J M Tromp; J van Laar; R Thijssen; J A Elias; A Malara; A Krippner-Heidenreich; J Silke; M Hj van Oers; E Eldering

doi:10.1038/cddis.2013.305

CLL cells are resistant to smac mimetics because of an inability to form a ripoptosome complex

Cell Death Dis. 2013 Aug 29;4(8):e782. doi: 10.1038/cddis.2013.305.

Authors

C Maas¹, J M Tromp, J van Laar, R Thijssen, J A Elias, A Malara, A Krippner-Heidenreich, J Silke, M Hj van Oers, E Eldering

Affiliation

¹ Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Abstract

In the lymph node (LN) environment, chronic lymphocytic leukemia (CLL) cells display increased NF-κB 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-α (TNFα)-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-κB activation and TNFα 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 TNFα 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-κB 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3T3 Cells
Animals
Baculoviral IAP Repeat-Containing 3 Protein
Biphenyl Compounds / pharmacology
CD40 Antigens / metabolism
CD40 Ligand / metabolism
Cell Death / drug effects
Drug Resistance, Neoplasm* / drug effects
Drug Resistance, Neoplasm* / genetics
Gene Expression Regulation, Neoplastic / drug effects
Humans
Inhibitor of Apoptosis Proteins / metabolism
Intracellular Signaling Peptides and Proteins / metabolism*
Leukemia, Lymphocytic, Chronic, B-Cell / genetics
Leukemia, Lymphocytic, Chronic, B-Cell / pathology*
Mice
Multiprotein Complexes / metabolism*
Mutation / genetics
NF-kappa B / metabolism
Nitrophenols / pharmacology
Piperazines / pharmacology
Proteasome Endopeptidase Complex / metabolism
Proteolysis / drug effects
Receptors, Tumor Necrosis Factor, Type I / metabolism
Receptors, Tumor Necrosis Factor, Type II / metabolism
Signal Transduction / drug effects
Signal Transduction / genetics
Sulfonamides / pharmacology
Tumor Necrosis Factor-alpha / biosynthesis
Ubiquitin-Protein Ligases

Substances

ABT-737
Biphenyl Compounds
CD40 Antigens
Inhibitor of Apoptosis Proteins
Intracellular Signaling Peptides and Proteins
Multiprotein Complexes
NF-kappa B
Nitrophenols
Piperazines
Receptors, Tumor Necrosis Factor, Type I
Receptors, Tumor Necrosis Factor, Type II
Sulfonamides
Tumor Necrosis Factor-alpha
CD40 Ligand
BIRC2 protein, human
BIRC3 protein, human
Baculoviral IAP Repeat-Containing 3 Protein
Ubiquitin-Protein Ligases
Proteasome Endopeptidase Complex