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Published on: September 1, 2018
Binding and uptake of immunostimulatory CpG oligodeoxynucleotides by human neuroblastoma cells
Liang-Hao Guo1, Hermann J Schluesener
1Institute of Brain Research, University of Tuebingen, D-72076, Tuebingen, Germany.
Abstract:
Oligodeoxynucleotides (ODNs) that contain unmethylated CpG dinucleotides (CpG-ODN) trigger a strong innate immune response in vertebrates. They have been used to eradicate experimental neuroblastoma, but a direct interaction of CpG-ODN with neuroblastoma cells has not been investigated. We have analyzed uptake, binding, and intracellular distribution of CpG-ODN in the neuroblastoma cells line SKNSH. Our results indicate that cellular uptake of CpG-ODN is dose, time, temperature, and energy dependent but independent of the CpG motif. After internalization, CpGODN localized to the cytoplasm and showed a typical speckled distribution pattern. The intracellular distribution pattern and binding proteins are CpG motif independent as well. Thus, CpG-ODNs are taken up by neuroblastoma cells by a nonspecific transfer mechanism for oligonucleotides and interact with intracellular proteins. These mechanisms might help us to understand the biodistribution of oligo within tumors and might be helpful in evaluating the therapeutic effects of oligonucleotides and rational drug design.
Insights
Oligodeoxynucleotides (CpG-ODN) are taken up by neuroblastoma cells via a non-specific mechanism. This uptake is independent of the CpG motif, suggesting broad therapeutic potential for oligonucleotide drugs.
Area of Science:
- Immunology
- Molecular Biology
- Oncology
Background:
- Oligodeoxynucleotides (ODNs) with unmethylated CpG motifs (CpG-ODN) stimulate innate immunity.
- CpG-ODN have shown efficacy in experimental neuroblastoma eradication.
- Direct interaction of CpG-ODN with neuroblastoma cells remains uninvestigated.
Purpose of the Study:
- To investigate the uptake, binding, and intracellular distribution of CpG-ODN in SK-NSH neuroblastoma cells.
- To determine the role of the CpG motif in these cellular interactions.
- To elucidate mechanisms relevant to oligonucleotide biodistribution and drug design in tumors.
Main Methods:
- Cellular uptake assays of CpG-ODN in SK-NSH cells.
- Analysis of CpG-ODN binding and intracellular localization.
- Investigation of dose, time, temperature, and energy dependence of uptake.
- Assessment of CpG motif independence.
Main Results:
- CpG-ODN cellular uptake is dependent on dose, time, temperature, and energy.
- Uptake is independent of the CpG motif.
- Internalized CpG-ODN localize to the cytoplasm in a speckled pattern.
- Intracellular distribution and binding proteins are CpG motif independent.
Conclusions:
- Neuroblastoma cells internalize CpG-ODN via a non-specific oligonucleotide transfer mechanism.
- CpG-ODN interact with intracellular proteins independent of the CpG motif.
- Understanding these mechanisms can inform oligonucleotide biodistribution and therapeutic drug design for neuroblastoma.
