Journal
REDOX BIOLOGY
Volume 21, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.redox.2018.101085
Keywords
RNA 3WJ nanoparticle; Knockdown of delta-5-desaturase; COX-2-catalyzed DGLA peroxidation; Tumor suppression; HCA-7 colony 29 cells
Categories
Funding
- National Cancer Institute [R15CA195499]
- National Institute of General Medical Sciences [P20GM109024]
- DOD Award [W81XWH-15-1-0052]
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We have previously demonstrated that DGLA treatment along with Delta-5-Desaturase (D5D) siRNA in various types of cancer cells enhances the formation of 8-HOA from COX-2-catalyzed DGLA peroxidation, which in turn inhibits cancer cell growth and migration. However, delivery of naked siRNA remains a formidable challenge due to its off-target effect. In this study, we employed RNA nanotechnology for specific delivery of D5D-siRNA to xenograft colon tumors using 3WJ RNA nanoparticles. When a targeting module, i.e., the EpCAM aptamer, was incorporated, the 3WJ pRNA nanoparticles were able specifically deliver D5D siRNA to human colon cancer HCA-7 cells both in vitro and in vivo, resulting in significant downregulation of D5D expression. Co-treatment with DGLA in combination with 3WJ-EpCAM-siRNA induced a higher DGLA/AA ratio and enhanced formation of 8-HOA at a threshold level, and in HCA-7 tumor-bearing mice, induced significant tumor suppression. We further confirmed that 8-HOA formation, promoted by COX-2-catalyzed DGLA peroxidation, inhibited HDAC and consequently induced apoptosis in tumor cells. Therefore, the 3WJ RNA nanoparticle system holds great promise as a suitable therapeutic delivery platform for colon cancer therapy.
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