학술논문
mTOR Inhibition Enhances Delivery and Activity of Antisense Oligonucleotides in Uveal Melanoma Cells.
Document Type
Academic Journal
Author
Dewaele S; OncoRNALab, Center for Medical Genetics (CMGG), Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium.; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.; Delhaye L; OncoRNALab, Center for Medical Genetics (CMGG), Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium.; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.; Center for Medical Biotechnology, VIB-Ghent University, Ghent, Belgium.; De Paepe B; Division of Pediatric Neurology and Metabolism, Department of Pediatrics, Ghent University Hospital, Ghent, Belgium.; Bogaert B; Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium.; Laboratory for General Biochemistry and Physical Pharmacy, Ghent University, Ghent, Belgium.; Martinez R; OncoRNALab, Center for Medical Genetics (CMGG), Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium.; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.; Anckaert J; OncoRNALab, Center for Medical Genetics (CMGG), Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium.; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.; Yigit N; OncoRNALab, Center for Medical Genetics (CMGG), Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium.; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.; Nuytens J; OncoRNALab, Center for Medical Genetics (CMGG), Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium.; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.; Van Coster R; Division of Pediatric Neurology and Metabolism, Department of Pediatrics, Ghent University Hospital, Ghent, Belgium.; Eyckerman S; Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium.; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.; Center for Medical Biotechnology, VIB-Ghent University, Ghent, Belgium.; Raemdonck K; Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium.; Laboratory for General Biochemistry and Physical Pharmacy, Ghent University, Ghent, Belgium.; Mestdagh P; OncoRNALab, Center for Medical Genetics (CMGG), Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium.; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.
Source
Publisher: Mary Ann Liebert, Inc Country of Publication: United States NLM ID: 101562758 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2159-3345 (Electronic) Linking ISSN: 21593337 NLM ISO Abbreviation: Nucleic Acid Ther Subsets: MEDLINE
Subject
Language
English
Abstract
Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Owing to a lack of effective treatments, patients with metastatic disease have a median survival time of 6-12 months. We recently demonstrated that the Survival Associated Mitochondrial Melanoma Specific Oncogenic Non-coding RNA (SAMMSON) is essential for UM cell survival and that antisense oligonucleotide (ASO)-mediated silencing of SAMMSON impaired cell viability and tumor growth in vitro and in vivo . By screening a library of 2911 clinical stage compounds, we identified the mammalian target of rapamycin (mTOR) inhibitor GDC-0349 to synergize with SAMMSON inhibition in UM. Mechanistic studies revealed that mTOR inhibition enhanced uptake and reduced lysosomal accumulation of lipid complexed SAMMSON ASOs, improving SAMMSON knockdown and further decreasing UM cell viability. We found mTOR inhibition to also enhance target knockdown in other cancer cell lines as well as normal cells when combined with lipid nanoparticle complexed or encapsulated ASOs or small interfering RNAs (siRNAs). Our results are relevant to nucleic acid treatment in general and highlight the potential of mTOR inhibition to enhance ASO and siRNA-mediated target knockdown.