Suppression of tobacco carcinogen-induced lung tumorigenesis by aerosol-delivered glycerol propoxylate triacrylate-spermine copolymer/short hairpin Rab25 rna complexes in female A/J mice

Abstract

Background: Rab25, a member of Rab family of small guanosine triphosphatase, is associated with progression of various types of human cancers, including lung cancer, the leading cause of cancer-associated deaths around the globe. Methods: In this study, we report the gene therapeutic effect of short hairpin Rab25 RNA (shRab25) on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis in female A/J mice. Initially, mice (6 weeks old) were injected with single dose of NNK (2mg/0.1mL saline/mouse) by intraperitoneal injection to induce the tumor. Eight weeks later, shRab25 was complexed with glycerol propoxylate triacrylate-spermine (GPT-SPE) copolymer and delivered into tobacco-induced lung cancer models through a nose-only inhalation system twice a week for 2 months. Results: GPT-SPE/shRab25 largely decreased the tobacco-induced tumor numbers and tumor volume in the lungs compared to GPT-SPE- or GPT-SPE/shScr-delivered groups. Remarkably, aerosol-delivered GPT-SPE/shRab25 significantly decreased the expression level of Rab25 and other prominent apoptosis-related proteins in female A/J mice. The apoptosis in these mice was determined by detecting the expression level of Bcl-2, proliferating cell nuclear antigen, Bax, and further confirmed by TUNEL assay. Conclusions: Our results strongly confirm the tumorigenic role of Rab25 in tobacco carcinogen-induced lung cancer and hence demonstrate aerosol delivery of shRab25 as a therapeutic target for lung cancer treatment.