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


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.


CONCLUSIONS
The cyclized oligopeptide reported here may be another option for the treatment of tumor burden in multiple myeloma.
Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, Korea.
Bo Mi
BM
Park
Institute of Biomedical Sciences, Yonsei University, Seoul, Korea.
Eun Jin
EJ
Kim
Division of Endocrinology and Endocrine Research Institute, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
Hee Jin
HJ
Nam
Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, Korea.
Dongdong
D
Zhang
Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, Korea.
Chu Hyun
CH
Bae
Institute of Biomedical Sciences, Yonsei University, Seoul, Korea.
Myeongmo
M
Kang
Department of Biochemistry, Yonsei University, Seoul, Korea.
Heeyoun
H
Kim
Department of Biochemistry, Yonsei University, Seoul, Korea.
Weontae
W
Lee
Centre for Immune Regulation, Institute of Immunology, University of Oslo and Oslo University Hospital, Oslo, Norway.
Bjarne
B
Bogen
Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, Korea.|Division of Endocrinology and Endocrine Research Institute, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea. lsk@yuhs.ac.
Sung Kil
SK
Lim
D000818:Animals; D001853:Bone Marrow / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D009101:Multiple Myeloma / Q000150:complications* / Q000473:pathology / Q000503:physiopathology*; D009842:Oligopeptides / Q000494:pharmacology*; D010006:Osteoblasts / Q000187:drug effects* / Q000473:pathology; D015398:Signal Transduction; D047368:Tumor Burden / Q000187:drug effects*; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin
C501127:Dkk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D009842:Oligopeptides; D051153:Wnt Proteins; D051176:beta Catenin
DKK1; Multiple myeloma; Wnt signaling; burden; oligopeptide; tumor