Abstract
The bone marrow microenvironment provides important signals for the survival and proliferation of hematopoietic and malignant cells. In multiple myeloma, plasma cells are surrounded by stromal cells including osteoblasts. These stromal cells protect multiple myeloma cells from apoptosis induced by chemotherapeutic agents. Osteoprotegerin (OPG), a soluble receptor of the cytokine TNF-related apoptosis-inducing ligand (TRAIL), is secreted by osteoblasts and has been implicated in the prevention of cell death induced by TRAIL in malignant cells. Previously, we have designed death receptor-specific TRAIL variants that induce apoptosis exclusively via one of its death receptors. Here, we have studied in detail the interaction between recombinant human (rhTRAIL) variants and OPG. We show that a DR5-specific variant (rhTRAIL D269H/E195R) displays a significantly decreased affinity to OPG. Furthermore, this rhTRAIL variant shows a much higher activity when compared with rhTRAIL WT and retains its effectiveness in inducing cell death in multiple myeloma cell lines, in the presence of OPG secreted by stromal cells. We also demonstrate that stromal cells are largely insensitive to high concentrations of this rhTRAIL variant. In conclusion, rhTRAIL D269H/E195R is a potential therapy for multiple myeloma due to its high effectiveness and diminished binding to OPG.
Highlights
The bone marrow environment secretes OPG and can thereby prevent tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in multiple myeloma
The mutant still showed ϳ70% binding efficiency to DR5-Fc even when competing with 2500 ng/ml OPG-Fc (Fig. 1C). These results indicate a decreased affinity of rhTRAIL D269H/E195R toward OPG, when compared with the affinity constants determined for rhTRAIL WT, and a lowered capacity of OPG-Fc to compete for DR5-Fc binding by this mutant, when compared with both rhTRAIL WT and rhTRAIL 4C7
To further improve the efficacy of rhTRAIL WT, we were recently successful in developing rhTRAIL variants that target cancer cells via either the DR5 or the DR4 receptor and induce apoptosis in various tumor cells, with improved effectiveness when compared with rhTRAIL WT [18, 19]
Summary
The bone marrow environment secretes OPG and can thereby prevent TRAIL-induced apoptosis in multiple myeloma. OPG is a soluble receptor that is secreted by osteoblasts residing in the bone marrow [15,16,17] This receptor has been shown to be involved in bone remodeling by binding to TNF superfamily-related protein receptor activator of NF-B ligand (RANKL). The impact of OPG in TRAIL-mediated apoptosis using rhTRAIL WT and death receptor-specific variants was further investigated in multiple myeloma cells, in the context of OPG released by their tumor microenvironment. We demonstrate that the lowered binding of a DR5-specific variant to OPG makes this variant insensitive to the interference in apoptosis mediated by this decoy receptor This makes the rhTRAIL D269H/E195R variant a promising agent for therapeutic intervention in multiple myeloma tumors
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