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

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)505-513
Number of pages9
JournalYonsei medical journal
Volume58
Issue number3
DOIs
Publication statusPublished - 2017 May

Bibliographical note

Funding Information:
MOPC315.BM.Luc cells and ab2.1-4 antibodies were obtained as generous gift from Bogen lab. This study was supported by Mid-career Research Program (NRF-2013R1A2A2A01068963) through NRF grant funded by the MEST; and Bo Mi Park, Dongdong Zhang, Chu Hyun Bae and Heeyoun Kim are recipients of Brain Korea 21 PLUS grant.

Publisher Copyright:
© Yonsei University College of Medicine 2017.

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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