Fusogenic-Oligoarginine Peptide-Mediated Delivery of siRNAs Targeting the CIP2A Oncogene into Oral Cancer Cells
| Autor: | Betsy Butler, Christopher C. Attaway, Andrew Jakymiw, Liliana Cantini, Lourdes M. Andino, Melissa L. Sokolosky |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Small interfering RNA
Oral Medicine Cancer Treatment lcsh:Medicine Arginine Biochemistry Autoantigens 03 medical and health sciences 0302 clinical medicine RNA interference Molecular cell biology Head and Neck Squamous Cell Carcinoma Oral Diseases Cell Line Tumor medicine Gene silencing Humans Gene Silencing RNA Small Interfering lcsh:Science Biology 030304 developmental biology Mouth neoplasm 0303 health sciences Multidisciplinary Oncogene Chemistry lcsh:R Intracellular Signaling Peptides and Proteins Cancer Cancers and Neoplasms Membrane Proteins Transfection Oncogenes medicine.disease Molecular biology Head and Neck Tumors 3. Good health Nucleic acids Oncology 030220 oncology & carcinogenesis Cancer cell Cancer research RNA Medicine lcsh:Q Mouth Neoplasms Research Article |
| Zdroj: | PLoS ONE PLoS ONE, Vol 8, Iss 9, p e73348 (2013) |
| ISSN: | 1932-6203 |
| Popis: | Despite a better understanding of the pathogenesis of oral cancer, its treatment outcome remains poor. Thus, there is a need for new therapeutic strategies to improve the prognosis of this disease. RNA interference (RNAi) appears to be a promising therapeutic tool for the treatment of many diseases, including oral cancer. However, an obstacle for RNAi-mediated therapies has been delivery, in particular, the retention of small interfering RNAs (siRNAs) in endosomes and their subsequent degradation in lysosomes, resulting in inefficient gene silencing. Thus, the current study examined the feasibility of designing and utilizing a peptide, termed 599, consisting of a synthetic influenza virus-derived endosome-disruptive fusogenic peptide sequence and a stretch of cationic cell-penetrating nona(D-arginine) residues, to deliver siRNAs into oral cancer cells and induce silencing of the therapeutic target, CIP2A, an oncoprotein overexpressed in various human malignancies including oral cancer. Increasing the 599 peptide-to-siRNA molar ratio demonstrated a higher binding capacity for siRNA molecules and enhanced siRNA delivery into the cytoplasm of oral cancer cells. In fact, quantitative measurements of siRNA delivery into cells demonstrated that a 50∶1 peptide-to-siRNA molar ratio could deliver 18-fold higher amounts of siRNAs compared to cells treated with siRNA alone with no significant long-term cytotoxic effects. Most importantly, the 599 peptide-mediated siRNA delivery promoted significant CIP2A mRNA and protein silencing which resulted in decreased oral cancer cell invasiveness and anchorage-independent growth. Together, these data demonstrate that a chimeric peptide consisting of a fusogenic sequence, in combination with cell-penetrating residues, can be used to effectively deliver siRNAs into oral cancer cells and induce the silencing of its target gene, potentially offering a new therapeutic strategy in combating oral cancer. |
| Databáze: | OpenAIRE |
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