Aptamer as a Molecular Tethering Agent Induces PrPC Aggregation and Degradation to Inhibit Melanoma Proliferation
Tiantian Xie
Molecular 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
Both authors contributed equally to this work.
Search for more papers by this authorYibin Zhang
Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008 China
Both authors contributed equally to this work.
Search for more papers by this authorNeng Ling
Molecular 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
Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang 325000, China, State Key Laboratory of Ophthalmology, Optometry and Vision Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China, Zhejiang Key Laboratory of Key Technologies for Visual Pathway Reconstruction，Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
Search for more papers by this authorYijun Yuan
Molecular 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
Search for more papers by this authorWeibin Liu
Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang 325000, China, State Key Laboratory of Ophthalmology, Optometry and Vision Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China, Zhejiang Key Laboratory of Key Technologies for Visual Pathway Reconstruction，Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
Search for more papers by this authorJunxiao Guo
Molecular 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
Search for more papers by this authorXianhua Wei
Molecular 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
Search for more papers by this authorTianhuan Peng
Molecular 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
Search for more papers by this authorZhiyan Wang
Molecular 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
Search for more papers by this authorJing Dai
Molecular 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
Search for more papers by this authorWenjing Chen
Molecular 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
Search for more papers by this authorMing Yan
Molecular 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
Search for more papers by this authorXiaoqiu Wu
Zhejiang Cancer Hospital, The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022 China
Search for more papers by this authorCorresponding Author
Wencan Wu
Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang 325000, China, State Key Laboratory of Ophthalmology, Optometry and Vision Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China, Zhejiang Key Laboratory of Key Technologies for Visual Pathway Reconstruction，Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
E-mail: [email protected]; [email protected]; [email protected]
Search for more papers by this authorCorresponding Author
Mao Ye
Molecular 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
E-mail: [email protected]; [email protected]; [email protected]
Search for more papers by this authorCorresponding Author
Weihong Tan
Molecular 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
Zhejiang Cancer Hospital, The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022 China
E-mail: [email protected]; [email protected]; [email protected]
Search for more papers by this authorTiantian Xie
Molecular 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
Both authors contributed equally to this work.
Search for more papers by this authorYibin Zhang
Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008 China
Both authors contributed equally to this work.
Search for more papers by this authorNeng Ling
Molecular 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
Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang 325000, China, State Key Laboratory of Ophthalmology, Optometry and Vision Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China, Zhejiang Key Laboratory of Key Technologies for Visual Pathway Reconstruction，Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
Search for more papers by this authorYijun Yuan
Molecular 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
Search for more papers by this authorWeibin Liu
Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang 325000, China, State Key Laboratory of Ophthalmology, Optometry and Vision Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China, Zhejiang Key Laboratory of Key Technologies for Visual Pathway Reconstruction，Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
Search for more papers by this authorJunxiao Guo
Molecular 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
Search for more papers by this authorXianhua Wei
Molecular 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
Search for more papers by this authorTianhuan Peng
Molecular 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
Search for more papers by this authorZhiyan Wang
Molecular 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
Search for more papers by this authorJing Dai
Molecular 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
Search for more papers by this authorWenjing Chen
Molecular 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
Search for more papers by this authorMing Yan
Molecular 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
Search for more papers by this authorXiaoqiu Wu
Zhejiang Cancer Hospital, The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022 China
Search for more papers by this authorCorresponding Author
Wencan Wu
Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang 325000, China, State Key Laboratory of Ophthalmology, Optometry and Vision Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China, Zhejiang Key Laboratory of Key Technologies for Visual Pathway Reconstruction，Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
E-mail: [email protected]; [email protected]; [email protected]
Search for more papers by this authorCorresponding Author
Mao Ye
Molecular 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
E-mail: [email protected]; [email protected]; [email protected]
Search for more papers by this authorCorresponding Author
Weihong Tan
Molecular 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
Zhejiang Cancer Hospital, The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022 China
E-mail: [email protected]; [email protected]; [email protected]
Search for more papers by this authorGraphical Abstract
We developed a molecular tethering agent, TTe-TTe, that binds to the octapeptide repeat region of glycosylated PrPC. TTe-TTe suppresses malignant melanoma proliferation by triggering PrPC to aggregate on the cell membrane surface, followed by its degradation. This versatile platform technology opens up new avenues for targeted protein degradation in a wide range of therapeutic applications, potentially advancing the field of drug discovery.
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.
Conflict of Interests
The authors declare no conflict of interest.
Open Research
Data Availability Statement
The data that support the findings of this study are available in the Supporting Information of this article.
Supporting Information
| Filename | Description |
|---|---|
| anie202425051-sup-0001-SuppMat.docx15.2 MB | Supporting Information |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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