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Cyclized Oligopeptide Targeting LRP5/6-DKK1 Interaction Reduces the Growth of Tumor Burden in a Multiple Myeloma Mouse Model

 Bo Mi Park  ;  Eun Jin Kim  ;  Hee Jin Nam  ;  Dongdong Zhang  ;  Chu Hyun Bae  ;  Myeongmo Kang  ;  Heeyoun Kim  ;  Weontae Lee  ;  Bjarne Bogen  ;  Sung-Kil Lim 
 Yonsei Medical Journal, Vol.58(3) : 505-513, 2017 
Journal Title
 Yonsei Medical Journal 
Issue Date
Animals ; Bone Marrow/metabolism* ; Cell Differentiation/drug effects ; Cell Line, Tumor ; Disease Models, Animal ; Intercellular Signaling Peptides and Proteins/metabolism* ; Mice ; Multiple Myeloma/complications* ; Multiple Myeloma/pathology ; Multiple Myeloma/physiopathology* ; Oligopeptides/pharmacology* ; Osteoblasts/drug effects* ; Osteoblasts/pathology ; Signal Transduction ; Tumor Burden/drug effects* ; Wnt Proteins/metabolism ; beta Catenin
DKK1 ; Multiple myeloma ; Wnt signaling ; burden ; oligopeptide ; tumor
PURPOSE: Dickkopf 1 (DKK1) has been extensively investigated in mouse models of multiple myeloma, which results in osteolytic bone lesions. Elevated DKK1 levels in bone marrow plasma and serum inhibit the differentiation of osteoblast precursors. Present pharmaceutical approaches to target bone lesions are limited to antiresorptive agents. In this study, we developed a cyclized oligopeptide against DKK1-low density lipoprotein receptor-related protein (LRP) 5/6 interaction and tested the effects of the oligopeptide on tumor burden. MATERIALS AND METHODS: A cyclized oligopeptide based on DKK1-LRP5/6 interactions was synthesized chemically, and its nuclear magnetic resonance structure was assessed. Luciferase reporter assay and mRNA expressions of osteoblast markers were evaluated after oligopeptide treatment. MOPC315.BM.Luc cells were injected into the tail vein of mice, after which cyclized oligopeptide was delivered subcutaneously 6 days a week for 4 weeks. RESULTS: The cyclized oligopeptide containing NXI motif bound to the E1 domain of LRP5/6 effectively on surface plasmon resonance analysis. It abrogated the Wnt-β-catenin signaling inhibited by DKK1, but not by sclerostin, dose dependently. RT-PCR and alkaline phosphatase staining showed increased expressions of osteoblast markers according to the treatment concentrations. Bioluminescence images showed that the treatment of cyclized oligopeptide reduced tumor burden more in oligopeptide treated group than in the vehicle group. CONCLUSION: The cyclized oligopeptide reported here may be another option for the treatment of tumor burden in multiple myeloma.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
강명모(Kang, Myengmo)
임승길(Lim, Sung Kil)
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