Aptamer as a Molecular Tethering Agent Induces PrP <sup>C</sup> Aggregation and Degradation to Inhibit Melanoma Proliferation
Abstract
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 (PrP C ) 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 PrP C protein levels by inducing membrane‐bound PrP C 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 PrP C . 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 PrP C , 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.
Article Details
Authors (16)
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
Yibin Zhang
Neng 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
Yijun Yuan
Weibin 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
Junxiao 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
Xianhua 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
Tianhuan 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
Zhiyan Wang
Jing Dai
Wenjing Chen
Ming Yan
Xiaoqiu Wu
Zhejiang Cancer Hospital, The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Hangzhou Institute of Medicine (HIM)
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
Mao Ye
Weihong Tan
Institute of Molecular Medicine (IMM), Department of Nephrology, Molecular Cell Laboratory for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Uremia Diagnosis and Treatment Center, State Key Laboratory of Systems Medicine for Cancer, Renji Hospital, School of Medicine, School of Chemistry and Chemical Engineering