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Aptamer as a Molecular Tethering Agent Induces PrPC Aggregation and Degradation to Inhibit Melanoma Proliferation
Tiantian Xie1, Yibin Zhang2, Neng Ling1,3
1Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo and Biosensing, Hunan Research Center of the Basic Discipline for Cell Signaling, College of Biology，College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan, 410082, China.
Abstract:
Melanoma, a malignant tumor originating from melanocytes, is the most aggressive and deadly form of skin cancer. Previous studies have revealed that the cellular prion protein (PrPC) is frequently overexpressed in melanoma, contributing to tumor progression. This study presents the first proof of concept evidence that nucleic acid aptamers can be used to construct a molecular tethering agent that regulates PrPC protein levels by inducing membrane-bound PrPC aggregation for antimelanoma therapy. Using a screening strategy combining cell-SELEX and cell-internalization SELEX, we obtained ssDNA aptamer, TT-1e, specifically binding to melanoma cells and tissues. We identified that the binding site of TT-1e is located at the octapeptide repeat region of glycosylated PrPC. Based on the binding characteristics of TT-1e, we engineered an aptamer-based molecular tethering agent TTe-TTe. We found that TTe-TTe induces aggregation of cell surface PrPC, promoting its internalization and facilitating its lysosomal degradation. This process resulted in the inhibition of AKT pathway activation. Importantly, in vivo studies confirmed the ability of TTe-TTe to target melanoma xenografts and suppress tumor growth through this unique mechanism. Our study presents a promising strategy for targeted melanoma therapy and introduces a paradigm-shifting approach for manipulating protein levels using aptamers as molecular tethering agents.
Insights
This study introduces aptamer-based molecular tethering agents to target melanoma. These agents aggregate cellular prion protein (PrPC), reducing its levels and inhibiting tumor growth for novel cancer therapy.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Melanoma, a deadly skin cancer, often overexpresses cellular prion protein (PrPC), driving tumor progression.
- Targeting PrPC presents a potential therapeutic strategy for melanoma.
- Developing novel agents to modulate PrPC levels is crucial for effective treatment.
Purpose of the Study:
- To develop and validate aptamer-based molecular tethering agents for antimelanoma therapy.
- To investigate the mechanism of action of these agents in regulating PrPC levels.
- To assess the efficacy of the developed agent in targeting melanoma cells and suppressing tumor growth.
Main Methods:
- Cell-SELEX and cell-internalization SELEX were employed to identify a specific ssDNA aptamer (TT-1e) targeting melanoma cells.
- An aptamer-based molecular tethering agent (TTe-TTe) was engineered based on TT-1e's binding characteristics.
- In vitro and in vivo studies were conducted to evaluate TTe-TTe's efficacy in targeting PrPC and inhibiting melanoma xenografts.
Main Results:
- The aptamer TT-1e specifically binds to glycosylated PrPC at the octapeptide repeat region on melanoma cells.
- TTe-TTe induces aggregation and lysosomal degradation of cell surface PrPC, inhibiting the AKT pathway.
- In vivo studies demonstrated that TTe-TTe effectively targets melanoma xenografts and suppresses tumor growth.
Conclusions:
- Aptamer-based molecular tethering agents represent a novel strategy for targeted melanoma therapy.
- This approach offers a paradigm-shifting method for manipulating protein levels using aptamers.
- The findings highlight the therapeutic potential of targeting PrPC aggregation in melanoma treatment.
