Abstract

The NEDD8-activating enzyme (NAE) inhibitor MLN4924 inhibits cullin-RING ubiquitin ligase complexes including the SKP1-cullin-F-box E3 ligase βTrCP. MLN4924 therefore inhibits also the βTrCP-dependent activation of the classical and the alternative NFĸB pathway. In this work, we found that a subgroup of multiple myeloma cell lines (e.g., RPMI-8226, MM.1S, KMS-12BM) and about half of the primary myeloma samples tested are sensitized to TNF-induced cell death by MLN4924. This correlated with MLN4924-mediated inhibition of TNF-induced activation of the classical NFκB pathway and reduced the efficacy of TNF-induced TNFR1 signaling complex formation. Interestingly, binding studies revealed a straightforward correlation between cell surface TNFR1 expression in multiple myeloma cell lines and their sensitivity for MLN4924/TNF-induced cell death. The cell surface expression levels of TNFR1 in the investigated MM cell lines largely correlated with TNFR1 mRNA expression. This suggests that the variable levels of cell surface expression of TNFR1 in myeloma cell lines are decisive for TNF/MLN4924 sensitivity. Indeed, introduction of TNFR1 into TNFR1-negative TNF/MLN4924-resistant KMS-11BM cells, was sufficient to sensitize this cell line for TNF/MLN4924-induced cell death. Thus, MLN4924 might be especially effective in myeloma patients with TNFR1+ myeloma cells and a TNFhigh tumor microenvironment.

Highlights

  • Multiple myeloma (MM) is a malignancy of differentiated blood B-cells

  • MLN4924 is less cytotoxic than carfilzomib and bortezomib on multiple myeloma cell lines

  • TNF is an extremely pleiotropic cytokine which exerts its cellular effects by stimulation of two receptors of the TNF receptor (TNFR) superfamily (TNFRSF): TNFR1 and TNFR227

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Summary

Introduction

Multiple myeloma (MM) is a malignancy of differentiated blood B-cells. This kind of malignancy localizes to the bone marrow leading to osteolysis, bone pain and impaired hematopoiesis[1]. A. The homodimeric and heterodimeric transcription factors of the NFκB family fulfill a variety of functions in different biological processes including immune response, development, cell growth and cell survival. Activation of NFκB transcription factors depends on proteolytic degradation/processing of IκB proteins or proteins containing an IκB-related domain that hinder nuclear translocation of NFκB transcription factors by intermolecular interaction or intramolecular binding, respectively[4,5]. Activation of NFκB transcription factors occurs via two distinct pathways: the classical and the alternative NFκB pathway[4,5]. The classical NFκB pathway depends on Official journal of the Cell Death Differentiation Association

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