Aerosol delivery of lentivirus-mediated O-glycosylation mutant osteopontin suppresses lung tumorigenesis in K-ras (LA1) mice

Abstract

Osteopontin (OPN) is a secreted glycophosphoprotein that has been implicated in the regulation of cancer development. The function of OPN is primarily regulated through post-translational modification such as glycosylation. As yet, however, the relationship between OPN glycosylation and lung cancer development has not been investigated. In this study, we addressed this issue by studying the effect of a triple mutant (TM) of OPN, which is mutated at three O-glycosylation sites, on lung cancer development in K-ras (LA1) mice, a murine model for human non-small cell lung cancer. Aerosolized lentivirus-based OPN TM was delivered into the lungs of K-ras (LA1) mice using a nose-only-inhalation chamber 3 times/wk for 4 wks. Subsequently, the effects of repeated delivery of OPN TM on lung tumorigenesis and its concomitant OPN-mediated signaling pathways were investigated. Aerosol-delivered OPN TM inhibited lung tumorigenesis. In addition, the OPN-mediated Akt signaling pathway was inhibited. OPN TM also decreased NF-kappa B activity and the phosphorylation of 4E-BP1, while facilitating apoptosis in the lungs of K-ras (LA1) mice. Our results show that aerosol delivery of OPN TM successfully suppresses lung cancer development in the K-ras (LA1) mouse model and, therefore, warrant its further investigation as a possible therapeutic strategy for non-small cell lung cancer.