Nanoparticle-based delivery of siDCAMKL-1 increases microRNA-144 and inhibits colorectal cancer tumor growth via a Notch-1 dependent mechanism

The development of effective drug delivery systems capable of transporting small interfering RNA (siRNA) has been elusive. We have previously reported that colorectal cancer tumor xenograft growth was arrested following treatment with liposomal preparation of siDCAMKL-1. In this report, we have util...

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Bibliographic Details
Published in:	Journal of nanobiotechnology 2011-09, Vol.9 (1), p.40-40, Article 40
Main Authors:	Sureban, Sripathi M, May, Randal, Mondalek, Fadee G, Qu, Dongfeng, Ponnurangam, Sivapriya, Pantazis, Panayotis, Anant, Shrikant, Ramanujam, Rama P, Houchen, Courtney W
Format:	Article
Language:	eng
Subjects:	Acquisitions & mergers Animals Binding sites Biotechnology cancer stem cells Carcinoma - drug therapy Colon Colorectal Neoplasms - drug therapy DCAMKL-1 Dipeptides - pharmacology Doublecortin-Like Kinases Down-Regulation Drug delivery systems Gene Expression Regulation, Neoplastic - drug effects HCT116 HCT116 Cells Health sciences Humans Intracellular Signaling Peptides and Proteins - pharmacology Kinases Mice Mice, Nude microRNA MicroRNAs - metabolism miR-144 Mortality Nanoparticles Nanoparticles - administration & dosage notch signaling Polylactic acid Protein Serine-Threonine Kinases - pharmacology Proteins Proto-Oncogene Mas Proto-Oncogene Proteins c-myc - metabolism Receptor, Notch1 - metabolism siRNA Statistical analysis Stem cells Tissue engineering Transcription Factors - metabolism tumor xenograft Up-Regulation Xenograft Model Antitumor Assays
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Summary:	The development of effective drug delivery systems capable of transporting small interfering RNA (siRNA) has been elusive. We have previously reported that colorectal cancer tumor xenograft growth was arrested following treatment with liposomal preparation of siDCAMKL-1. In this report, we have utilized Nanoparticle (NP) technology to deliver DCAMKL-1 specific siRNA to knockdown potential key cancer regulators. In this study, mRNA/miRNA were analyzed using real-time RT-PCR and protein by western blot/immunohistochemistry. siDCAMKL-1 was encapsulated in Poly(lactide-co-glycolide)-based NPs (NP-siDCAMKL-1); Tumor xenografts were generated in nude mice, treated with NP-siDCAMKL-1 and DAPT (γ-secretase inhibitor) alone and in combination. To measure let-7a and miR-144 expression in vitro, HCT116 cells were transfected with plasmids encoding the firefly luciferase gene with let-7a and miR-144 miRNA binding sites in the 3'UTR. Administration of NP-siDCAMKL-1 into HCT116 xenografts resulted in tumor growth arrest, downregulation of proto-oncogene c-Myc and Notch-1 via let-7a and miR-144 miRNA-dependent mechanisms, respectively. A corresponding reduction in let-7a and miR-144 specific luciferase activity was observed in vitro. Moreover, an upregulation of EMT inhibitor miR-200a and downregulation of the EMT-associated transcription factors ZEB1, ZEB2, Snail and Slug were observed in vivo. Lastly, DAPT-mediated inhibition of Notch-1 resulted in HCT116 tumor growth arrest and down regulation of Notch-1 via a miR-144 dependent mechanism. These findings demonstrate that nanoparticle-based delivery of siRNAs directed at critical targets such as DCAMKL-1 may provide a novel approach to treat cancer through the regulation of endogenous miRNAs.
ISSN:	1477-3155 1477-3155