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Research Papers:

Sensitization of neuroblastoma for vincristine-induced apoptosis by Smac mimetic LCL161 is attended by G2 cell cycle arrest but is independent of NFκB, RIP1 and TNF-α

Doerte Langemann, Magdalena Trochimiuk, Birgit Appl, Patrick Hundsdoerfer, Konrad Reinshagen and Georg Eschenburg _

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Oncotarget. 2017; 8:87763-87772. https://doi.org/10.18632/oncotarget.21193

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Abstract

Doerte Langemann1, Magdalena Trochimiuk1, Birgit Appl1, Patrick Hundsdoerfer2, Konrad Reinshagen1 and Georg Eschenburg1

1Department of Pediatric Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Department of Pediatric Oncology/Hematology, Charité - Universitätsmedizin Berlin, Berlin, Germany

Correspondence to:

Georg Eschenburg, email: [email protected]

Keywords: neuroblastoma, LCL161, vincristine, NFκB, G2 cell cycle arrest

Received: June 27, 2017     Accepted: August 14, 2017     Published: September 23, 2017

ABSTRACT

We demonstrated sensitization for chemotherapy by Smac mimetic (SM) LCL161, a potent antagonist of inhibitor of apoptosis proteins (IAP), in neuroblastoma (NB). Vinca alkaloids, particularly vincristine (VCR), displayed the strongest impact on inhibition of proliferation and apoptosis induction in combination with LCL161. The underlying signaling pathways remain elusive, though. LCL161 induces a quick degradation of cellular IAP 1 (cIAP-1). Combination of LCL161 with VCR had only marginal effects on X-linked IAP (XIAP) protein expression. Cell death is accompanied by activation of intrinsic (caspase-9 and MMP) and extrinsic (caspase-8) pathways of apoptosis, repression of migratory potential and cell cycle arrest in G2 phase.

LCL161-induced cIAP degradation leads to activation of non-canonical and blockade of canonical NF-κB pathways but not induction of apoptosis. Surprisingly NF-κB and TNF-α signaling is negligible for VCR- and VCR/LCL161-induced apoptosis since chemical inhibition of NF-κB using BAY-7085 and PBS-1086, as well as application of TNF-α blocking antibody Humira (adalimumab) has no relevant effect on cell death. Recently formation of a TNF-α-independent complex (ripoptosome) consisting of RIP1, FADD and caspase-8 following IAP inhibition by SM has been described. However, targeting of RIP1 by Necrostatin was not sufficient to influence apoptosis induced by VCR/LCL161.


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