Cyclized Oligopeptide Targeting LRP5/6-DKK1 Interaction Reduces the Growth of Tumor Burden in a Multiple Myeloma
Bo Mi Park1, Eun Jin Kim2, Hee Jin Nam3
1Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, Korea.
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.
Insights
A novel cyclized oligopeptide targeting Dickkopf 1 (DKK1) effectively reduced multiple myeloma tumor burden in mice. This peptide promotes osteoblast differentiation, offering a potential new therapeutic strategy beyond antiresorptive agents.
Area of Science:
- Biochemistry
- Oncology
- Pharmacology
Background:
- Multiple myeloma frequently causes osteolytic bone lesions due to elevated Dickkopf 1 (DKK1).
- DKK1 inhibits osteoblast precursor differentiation, and current treatments primarily use antiresorptive agents.
- Targeting the DKK1-low density lipoprotein receptor-related protein (LRP) 5/6 interaction presents a novel therapeutic avenue.
Purpose of the Study:
- To develop and evaluate a cyclized oligopeptide designed to inhibit the DKK1-LRP5/6 interaction.
- To assess the oligopeptide's effects on osteoblast differentiation and multiple myeloma tumor burden in a preclinical model.
Main Methods:
- Chemical synthesis and structural assessment of a cyclized oligopeptide targeting DKK1-LRP5/6.
- In vitro evaluation using luciferase reporter assays and assessment of osteoblast marker gene expression.
- In vivo studies involving MOPC315.BM.Luc multiple myeloma cell injection and oligopeptide administration in mice.
Main Results:
- The synthesized oligopeptide effectively bound to LRP5/6 and abrogated DKK1-mediated Wnt-β-catenin signaling inhibition.
- Oligopeptide treatment dose-dependently increased osteoblast marker expression.
- Bioluminescence imaging demonstrated a significant reduction in tumor burden in oligopeptide-treated mice compared to controls.
Conclusions:
- The developed cyclized oligopeptide shows promise as a therapeutic agent for multiple myeloma.
- This approach offers a potential new treatment strategy by targeting DKK1 and promoting bone formation.
