A Novel Aptamer LL4A Specifically Targets Vemurafenib-Resistant Melanoma through Binding to the CD63 Protein
Melanoma is a highly aggressive tumor with a poor prognosis, and half of all melanoma patients harbor BRAF mutations. A BRAF inhibitor, vemurafenib (PLX4032), has been approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) to treat advanced melanoma patients with B...
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| Format: | Article |
| Language: | English |
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Elsevier
2019-12-01
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| Series: | Molecular Therapy: Nucleic Acids |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253119303014 |
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doaj-8b39ca053fd94a59b7bb3096f227533f |
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Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Hui Li Juan Liu Xiaojuan Xiao Shuming Sun Hui Zhang Yibin Zhang Weihua Zhou Bin Zhang Mridul Roy Hong Liu Mao Ye Zi Wang Feng Liu-Smith Jing Liu |
| spellingShingle |
Hui Li Juan Liu Xiaojuan Xiao Shuming Sun Hui Zhang Yibin Zhang Weihua Zhou Bin Zhang Mridul Roy Hong Liu Mao Ye Zi Wang Feng Liu-Smith Jing Liu A Novel Aptamer LL4A Specifically Targets Vemurafenib-Resistant Melanoma through Binding to the CD63 Protein Molecular Therapy: Nucleic Acids |
| author_facet |
Hui Li Juan Liu Xiaojuan Xiao Shuming Sun Hui Zhang Yibin Zhang Weihua Zhou Bin Zhang Mridul Roy Hong Liu Mao Ye Zi Wang Feng Liu-Smith Jing Liu |
| author_sort |
Hui Li |
| title |
A Novel Aptamer LL4A Specifically Targets Vemurafenib-Resistant Melanoma through Binding to the CD63 Protein |
| title_short |
A Novel Aptamer LL4A Specifically Targets Vemurafenib-Resistant Melanoma through Binding to the CD63 Protein |
| title_full |
A Novel Aptamer LL4A Specifically Targets Vemurafenib-Resistant Melanoma through Binding to the CD63 Protein |
| title_fullStr |
A Novel Aptamer LL4A Specifically Targets Vemurafenib-Resistant Melanoma through Binding to the CD63 Protein |
| title_full_unstemmed |
A Novel Aptamer LL4A Specifically Targets Vemurafenib-Resistant Melanoma through Binding to the CD63 Protein |
| title_sort |
novel aptamer ll4a specifically targets vemurafenib-resistant melanoma through binding to the cd63 protein |
| publisher |
Elsevier |
| series |
Molecular Therapy: Nucleic Acids |
| issn |
2162-2531 |
| publishDate |
2019-12-01 |
| description |
Melanoma is a highly aggressive tumor with a poor prognosis, and half of all melanoma patients harbor BRAF mutations. A BRAF inhibitor, vemurafenib (PLX4032), has been approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) to treat advanced melanoma patients with BRAFV600E mutation. However, the efficacy of vemurafenib is impeded by adaptive resistance in almost all patients. In this study, using a cell-based SELEX (systematic evolution of ligands by exponential enrichment) strategy, we obtained a DNA aptamer (named LL4) with high affinity and specificity against vemurafenib-resistant melanoma cells. Optimized truncated form (LL4A) specifically binds to vemurafenib-resistant melanoma cells with dissociation constants in the nanomolar range and with excellent stability and low toxicity. Meanwhile, fluorescence imaging confirmed that LL4A significantly accumulated in tumors formed by vemurafenib-resistant melanoma cells, but not in control tumors formed by their corresponding parental cells in vivo. Further, a transmembrane protein CD63 was identified as the binding target of aptamer LL4A using a pull-down assay combined with the liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. CD63 formed a supramolecular complex with TIMP1 and β1-integrin, activated the nuclear factor кB (NF-кB) and mitogen-activated protein kinase (MAPK) signaling pathways, and contributed to vemurafenib resistance. Potentially, the aptamer LL4A may be used diagnostically and therapeutically in humans to treat targeted vemurafenib-resistant melanoma. Keywords: melanoma, vemurafenib-resistant, aptamer, LL4A, CD63 |
| url |
http://www.sciencedirect.com/science/article/pii/S2162253119303014 |
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1725051255044177920 |
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doaj-8b39ca053fd94a59b7bb3096f227533f2020-11-25T01:38:57ZengElsevierMolecular Therapy: Nucleic Acids2162-25312019-12-0118727738A Novel Aptamer LL4A Specifically Targets Vemurafenib-Resistant Melanoma through Binding to the CD63 ProteinHui Li0Juan Liu1Xiaojuan Xiao2Shuming Sun3Hui Zhang4Yibin Zhang5Weihua Zhou6Bin Zhang7Mridul Roy8Hong Liu9Mao Ye10Zi Wang11Feng Liu-Smith12Jing Liu13Molecular Biology Research Center, School of Life Sciences, Central South University, Changsha 410078, ChinaMolecular Biology Research Center, School of Life Sciences, Central South University, Changsha 410078, ChinaMolecular Biology Research Center, School of Life Sciences, Central South University, Changsha 410078, ChinaMolecular Biology Research Center, School of Life Sciences, Central South University, Changsha 410078, ChinaMolecular Science and Biomedicine Laboratory, State Key Laboratory for Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Collaborative Innovation Center for Chemistry and Molecular Medicine, Hunan University, Changsha 410082, ChinaMolecular Science and Biomedicine Laboratory, State Key Laboratory for Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Collaborative Innovation Center for Chemistry and Molecular Medicine, Hunan University, Changsha 410082, ChinaMolecular Biology Research Center, School of Life Sciences, Central South University, Changsha 410078, China; Department of Obstetrics and Gynecology, People’s Hospital of Xiangxi Tujia and Miao Autonomous Prefecture, Hunan, Jishou 410006, ChinaDepartment of Histology and Embryology, Xiangya School of Medicine, Central South University, Changsha 410013, ChinaMolecular Science and Biomedicine Laboratory, State Key Laboratory for Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Collaborative Innovation Center for Chemistry and Molecular Medicine, Hunan University, Changsha 410082, ChinaThe First Xiangya Hospital, Central South University, Changsha 410078, ChinaMolecular Science and Biomedicine Laboratory, State Key Laboratory for Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Collaborative Innovation Center for Chemistry and Molecular Medicine, Hunan University, Changsha 410082, ChinaMolecular Biology Research Center, School of Life Sciences, Central South University, Changsha 410078, China; The First Xiangya Hospital, Central South University, Changsha 410078, China; Corresponding author: Zi Wang, Molecular Biology Research Center, School of Life Sciences, Central South University, Changsha 410078, China.Molecular Biology Research Center, School of Life Sciences, Central South University, Changsha 410078, China; Department of Epidemiology, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA; Corresponding author: Feng Liu-Smith, Molecular Biology Research Center, School of Life Sciences, Central South University, Changsha 410078, China.Molecular Biology Research Center, School of Life Sciences, Central South University, Changsha 410078, China; Corresponding author: Jing Liu, Molecular Biology Research Center, School of Life Sciences, Central South University, Changsha 410078, China.Melanoma is a highly aggressive tumor with a poor prognosis, and half of all melanoma patients harbor BRAF mutations. A BRAF inhibitor, vemurafenib (PLX4032), has been approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) to treat advanced melanoma patients with BRAFV600E mutation. However, the efficacy of vemurafenib is impeded by adaptive resistance in almost all patients. In this study, using a cell-based SELEX (systematic evolution of ligands by exponential enrichment) strategy, we obtained a DNA aptamer (named LL4) with high affinity and specificity against vemurafenib-resistant melanoma cells. Optimized truncated form (LL4A) specifically binds to vemurafenib-resistant melanoma cells with dissociation constants in the nanomolar range and with excellent stability and low toxicity. Meanwhile, fluorescence imaging confirmed that LL4A significantly accumulated in tumors formed by vemurafenib-resistant melanoma cells, but not in control tumors formed by their corresponding parental cells in vivo. Further, a transmembrane protein CD63 was identified as the binding target of aptamer LL4A using a pull-down assay combined with the liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. CD63 formed a supramolecular complex with TIMP1 and β1-integrin, activated the nuclear factor кB (NF-кB) and mitogen-activated protein kinase (MAPK) signaling pathways, and contributed to vemurafenib resistance. Potentially, the aptamer LL4A may be used diagnostically and therapeutically in humans to treat targeted vemurafenib-resistant melanoma. Keywords: melanoma, vemurafenib-resistant, aptamer, LL4A, CD63http://www.sciencedirect.com/science/article/pii/S2162253119303014 |